Physiological Assessment of Cardiac Autonomic

Vol. 2 No. I, March, 1999

Suez Canal Univ Med J

61 -72

Physiological Assessment of Cardiac Autonomic Reflexes in Diabetics Samy M. Makary, Hamdy A. Selim', Yasser M. El-Wazir, Abd El-Ariz Mahmoud Departments of Physiology and Medicine I, Faculty of Medicine, Suez Canal University

whereas it deteriorated in conventionally treated patients?'.

Introduction

One of the most leading public health problems in the world is diabetes mellitus. It affects all the body systems especially the nervous and the cardiovascular systems. Thus, many researchers were concerned with studying the effect of hyperglycemia on the nervous system and nerve conduction. It was noted that the commonest type of diabetic neuropathy in both insulin dependant and non-insulin dependant diabetes mellitus is symmetric sensory and autonomic polyneuropathy'!'.

Early features of CAD, are abnormalities of the parasympathetic reflexes as heart rate (RR) response to deep breathing which are blocked by atropine. Sympathetic efferent functions, as blood pressure (BP) response to change in posture and isometric exercise, tend to become abnormal at a later stage. In 5 years prospective study of diabetic subjects with abnormalities in autonomic responses to the above maneuvers, the mortality rate was found to be 50% within 3 years after detection. The mortality rate increased especially if there are CAD symptoms as postural hypotension, gustatory sweating, peripheral edema, impotence, or loss of hypoglycemic

It was obvious that autonomic dysfunction

(AD) treated by strict glycemic control as pancreatic transplantation or continuous subcutaneous insulin infusion was stabilized

symptoms". 61

Samy M. Makary, et al.

62

The immediate heart rate response to lying down was used to detect some abnormalities in diabetics with apparently normal reflexes. It is useful to use it in conjunction with the currently established simple tests for cardio-autonomic reflexes (CAR)(4). Braune and Geisendorferv" reported that reproducibility of CAR test results was good and statistical analysis showed a significant difference between diabetics and normal subjects. Evidence of autonomic neuropathy may be present at the time. of diagnosis of diabetes or may appear within 1-2 years of diagnosis. The . precise relationship of AD to the duration of diabetes has not been established. The abnormalities of CAR are 17% in the overall diabetics, with more abnormalities in those aged 40-49 years and those with duration for more than 20 years. The available evidence from the various prevalence studies, however, suggests that similar percentages of abnormalities are found in both IDDM and NIDDM. Thus, it is not the type of diabetes that is of relevance when considering autonomic damage, but rather the metabolic abnormalities consequent on a raised blood sugar level(6). A statistically significant association was observed between AD and the presence of the following symptoms: dizziness on standing, dysphasia, vomiting, diarrhea, fecal incontinence, gustatory sweating, urinary retention, numbness and hyperthesia of the feet. The course of symptoms could be fluctuant as assessed by CAR tests'?', The place of non-invasive cardiovascular reflex tests is now firmly established for the objective bedside assessment of diabetic AD. In diabetes mellitus, disordered autonomic function, although not always clinically apparent, can be detected by these tests. Cardio-autonomic reflex tests give insights into the pathophysiology of diabetic AD. Assessment of the cardiac autonomic reflexes may help to detect early abnormalities of

autonomic reflexes in asymptomatic diabetics, and to monitor its course in symptomatic patientsv". The aim of the present study was to describe the heart rate variation and blood pressure change in response to physiological changes in posture, respiratory activity and muscle tone as a part of cardiac autonomic reflexes in diabetics. Also, the possible correlation between the physiological responses to cardiac autonomic reflexes and other factors as duration of diabetes, glycosylated hemoglobin, total body mass index and age was investigated.

Subjects and Methods Seventy-seven diabetic subjects free of organic cardiac, renal, or CNS disease (confirmed by a routine medical history, clinical examination, ECG, urine analysis, and serum creatinine), and twenty-three non-diabetic normal subjects were subjected to the CAR tests. Subjects receiving diuretics, cardiac or CNS drugs were excluded from the study because of possible interference with test results. All subjects were informed about the procedure of tests and their safety. Oral consent was taken from them before tests were done. Assessment of cardio-autonomic reflexes In the sitting position, ECG electrodes were connected to each subject. Lead II was recorded only to assess the RR interval, then the following parameters were assessed: 1. Heart rate response to deep breathing: In the sitting position, each subject breathed temporally in respiratory cycles that were adjusted to be one cycle every 10 seconds, for 3 cycles. Heart rate response to deep breathing was calculated as the ratio between the maximum heart rate during expiration to the minimum heart rate during inspiration [Ell]. Ratio < 1.05 was considered ahnormalv". 2. Heart rate response to Valsalva maneuver:

Physiological Assessment of Cardiac Reflexes in Diabetics

In the sitting position, each subject blew into a mouthpiece of a rubber tube connected to a sphygmomanometer. The subject blew to a pressure of 40 mmHg for 15 seconds. Valsalva ratio was calculated as the ratio of the longest RR interval around the 20th beat after release, to the shortest RR interval during the maneuver. Results were considered abnormal if s 1.2(9). 3. Heart rate response to lying down: The subject was asked to lie down from the standing position, while a continuous ECG monitoring to the variation of the RR interval was made. SL t was calculated as the ratio of the maximum RR interval before lying down (in standing-up position) to the minimum RR interval during the first 5 beats after lying down. SL2 was calculated as the ratio of the maximum RR interval among the beats from 20th to 25th after lying to the minimum RR interval during the first 5 beats after lying down. SL t < 1.1 and S~ < 1.23 were considered abnormalv".

4. Response of heart rate and BP to standing-up: The subject was asked to stand-up from the lying position, then an ECG monitoring to the variation of the RR interval was recorded. The HR response to standing-up was calculated as the ratio of the maximum RR interval around beat 30th to the minimum RR interval around beat 15th after standing-up (US HR ratio). Ratio ~ 1 was considered abnormali?', Blood pressure response to standing-up was calculated as the drop of systolic blood pressure (SBP) measured after 1 second from the change in position. Decrease of ~ 30 mmHg was taken as abnormal'?'. 5. Blood pressure response to sustained handgrip: In the sitting position, each subject was requested to squeeze sphygmomanometer cuff at his maximum power. The pressure inside the cuff during the maximum handgrip was recorded. The

63

subject was asked to maintain pressure level of 30 % of the maximum power as long as he can tolerate. Blood pressure response to sustained handgrip was calculated as the difference in DBP before starting and immediately before the subject released his squeeze to the cuff. Results were counted as abnormal if the increase in DBP was s 10 mmflg'?'. AD was identified as the presence of at least one abnormal test(8). Measurements: Weight (Wt) in kilograms (kg) and height (Ht) in meters (m) were measured using a commercial scale for both parameters. Total body mass index (TBMI) was calculated according to the following formula: TBMI = Wt (kg) I Ht2 (m). The upper normal limit, used in the current study, was 25 kglm2(10). Laboratory tests: Glycosylated hemoglobin: It was measured by ion-exchange resin procedure using a commercial kit [Stanbio, Texas, USA, No 0350]. The quoted norma. range was: 4.6 - 7

% (II).

"

Serum creatinine: It' was measured by spectrophotometry using a commercial kit (Bromiera). The quoted normal ranges were: < 1.2 mgldL for males, and < 1.1 mgldL for females'I!'. STATISTICAL NALYSIS

The data were· presented as means ± standard deviations. The data were analyzed by a computer program [SPSS]. ANDVA was used to test the significance of the difference among groups. In case a significant difference was detected, Scheffe test was applied to identify the. direction of difference. P value ~ 0.05 was considered significant. Correlation coefficient (r) was used to test the correlation between two variables. Existence of statistical correlation was postulated whenever r >2.5.

64

Samy M. Makary, et a1.

Results Seventy-seven diabetic subjects were compared to twenty-three age and sex matched healthy control subjects. The diabetic group was further subdivided into two subgroups according to the results of the CAR tests: diabetics without CAD in which all CAR tests were normal (n=12) and diabetics with CAD (n=65). Table (I) shows the characteristics of the study groups. Results revealed no statistically significant difference in the age and height. However, a significant increase was detected in weight (p=O.03) and TBMI (p=O.01) in the diabetic group with CAD who were having significantly higher values than those of diabetics without CAD and control subjects. The results of CAR tests in the study groups are shown in table (II). Comparison among them revealed that there was a significant statistical difference in ElI test (p=O.02), Valsalva test (p=O.Ol), LS test (p=O.05), SL 1 test (p=O.03), S~ test (p=O.02),

standing SBP (p=O.OOl), and sustained handgrip DBP test (p=O.OI). Scheffe test revealed that the difference was between diabetics having AD and the other two groups in five tests which were: Valsalva test, LS HR ratio, SL1 ratio, SL2 ratio and the decrease in SBP after standing-up. In the other two tests; which were FJI HR ratio and the increase in DBP with handgrip, the control subjects were different from the other two groups. The correlation of CAR tests to age, weight, height, TBMI, duration of diabetes and level of glycosylated hemoglobin are shown in table (III). Nearly all of the 7 CAR tests, used in the current study, showed significant correlation with TBMI, glycosylated hemoglobin and absolute weight. Some of the CAR tests showed correlation with age and duration of disease. All correlation values were negative except those with the decrease in SBP upon standing-up. On the other hand, no significant correlation was found with height. Changes in RR intervals during some of the CAR tests are shown in figures'!' 2).

Table (I): Characteristics of the control and diabetic groups.

Age (years)

Weight (Kg)

Height (m)

TBMI (Kglm2)

Control group

Diabetic without CAD

Diabetic with CAD

(n 23)

(n=12)

(n=65)

4.20.4±

35.17±

44.49

13.24

12.85

11..57

62.75±

63.68±

48.21±

6.09

5.70

17.31*

1.68±

1.65±

1.66±

0.09

0.06

0.08

22.37±

23.38±

30.21±

2.01

5.67*

2.59 Data are expressed as means ± SD

* Marked value is significantly different as compared to the other two groups AD = Autonomic Dysfunction TBMI = Total Body Mass Index [Normal < 25 Kg/m2]

p value

NS

0.03

NS

0.01

Physiological Assessment of Cardiac Reflexes in Diabetics 65 Table (II): Results of cardio-autonomic reflex tests in control and diabetic groups Control group

Diabetic without CAD

Diabetic with CAD

(n 23)

(n=12)

(n=65)

p value

PiI HR Ratio

1.37±0.18*

1.19±O.1

1.13±O.09

0.02

Valsalva HR ratio

1.42±0.24

1.39±0.197

1.15±O.24*

0.01

US HR Ratio

1.14±0.09

1.13±0.14

1.07±O.07*

0.05

SL 1 HR Ratio

1.23±0.08

1.20±0.09

1.08±O.1*

0.03

SLz HR Ratio ..i. SBP after Standing-up (mmHg)

1.43±0.15

1.14±0.16

1.23±O.13*

0.02

1.67±3.27

2.65±8.99

16.08±13.79*

0.001

i DBP with sustained

43.75±7.42*

27.39±10.09

23.08±10.40

0.01

Handgrip (mmHg)

Data are expressed as means ± SD * Marked value is significantly different as compared to the other two groups CAD = Autonomic Dysfunction

FlI = Expiration I Inspiration

HR = Heart Rate

SL = Standing to Lying

SBP = Systolic Blood Pressure

DBP = Diastolic Blood Pressure

LS = Lying to Standing

Table (III): Correlation of the cardioautonomic reflexes to characteristics of patients and indices of the diabetic state. E1IHR

Valsalva HR

Standing-up

SL t

Ratio

Ratio

HRRatio

HE Ratio

,J,SBPafter

tDBP after

Standing-up

handgrip

(mmHg)

(mmHg)

p

r

p

r

p

r

p

r

p

r

p

0.001 -0.1

NS

-0.2

0.05

-0.2

NS

-0.5

0.00

0.3

0.00

-0.3

0.02

-0.3

0.01

-0.3

0.004 -0.4

0.00

-0.3

0.01

-0.5

0.00

0.5

0.00

-0.6

0.00

0.1

NS

-0.1

NS

NS

-0.1

NS

0.1

NS

-0.01

NS

-0.04

NS

r

p

Age (years)

-0.4

TBMI (Kglm2) Height (m) Weight (Kg)

SLz HR Ratio

-0.2

0.04

r

-0.3

0.2

0.004 -0.3

0.01

-0.4

0.00

-0.4

0.00

0.5

0.00

-0.6

0.0

0.32

0.00

-0.33

0.00

Duration ofDM (years)

-0.3

0.01

-0.2

NS

-0.23

0.05

-0.3

0.02

-0.3

0,01

Duration of treatment (years)

-0.2

0.04

-0.1

NS

-0.2

0.05

-0.2

0.04

-0.2

0.05

0.28

0.01

-0.3

0.02

G1ycosylated

-0.3

0,01

-0.3

0.00

-0.3

0.00

-0.3

0.02

-0.5

0.00

0.54

0.00

-0.59

0.00

hemoglobin (%) r: Correlation coefficient

p: p value of r

66

Samy M. Makary, et aI.

1.6,

-'-

--.

1.4

I II

. . 0.8

~

i i

0.8

0.4

During

After

0.2

0'---1

2

3

4

........ 5

8

7

8

-

0 10 11 12 13 14 15 18 17 18

to 20 21 BNts

--'

22 23 24 25 2Il 27 2Il 29 30 31 32 33 34 35 35 'S7 311 3ll ~~

_ .....

..... ~ _ A D ±:~~AD...~ ..

Figure (l): Change in mean values of RR interval during Valsalva and after it. The ratio of the longest RR interval around the 20th beat beat after release, to the shortest RR interval during the maneuver is significantly lower in diabetics compared to control subjects (p=O.OI).

1.4

r-------------------------

--,

12

OA

oL 1

- _ _--' 2.

3

4

S

8

7

8

•

to

11 12 "

14 '5

,.

17 II

18 20

2f

22 23 24 •

•

27 •

2ll 3D :s1 Sl

:D

Figure (2): Change in RR interval after standing-up. The ratio of the longest RR interval around the 30th beat to the shortest RR around 15th beat after standing-up is significantly lower in both diabetic groups compared to the control subjects (p=O.05).


Discussion The activity of the autonomic nervous system is of crucial importance in the moment to moment regulation of heart rate and blood vessels resistance, thereby controlling arterial pressure, cardiac output and tissue perfusion (12). Assessment of cardiovascular autonomic nerve damage can be made from the combined results of simple non-invasive cardio-autonomic tests'?'. Our results showed that the mean values of Ell ratio of the diabetic group with or without CAD were significantly lower than in control subjects. Ell ratio is a ratio between expiration-induced bradycardia to inspiration-induced tachycardia. Heart rate increased during inspiration because of the decrease in the vagal activity to the heart, a response that can be blocked by atropine. Also, during inspiration, there was an increase in the venous return, which induced tachycardia by the Bainbridge effect. The reverse process is induced during expiration, with increase in the vagal tone and so the heart rate decreases-". The decrease in ElI ratio in the diabetic group may be due to the decrease in the vagal tone to the heart (bradycardia phase) during the expiration. This result showed the effect of diabetes on the cardiac vagal reflex, and to what extent it was affected in the diabetic subjects. These findings were also previously shown by others(13-1S). The mean value of HR ratio between post-Valsalva bradycardia to within test tachycardia was significantly lower in the studied diabetics with CAD in comparison to diabetics without CAD and the control subjects. However, it was clear that even diabetics without CAD had a mean value lower than the control subjects but the difference did not mount to the statistical significance. The overshooting of the BP at the end of the maneuver stimulates the baroreceptors, causing a reflex bradycardia

67

and a drop in BP to a normal level(l6). Pharmacological studies showed that the heart rate responses can be abolished by atropine, suggesting that these changes reflect cardiac parasympathetic integrity in response to Valsalva maneuver-", The blood pressure changes can be abolished by total cardiac and peripheral autonomic blockade'!". The abnormality detected in that reflex, observed in our results, may be due to the failure of the blood pressure to overshoot after termination of the maneuver with a resultant decrease or even loss in post test bradycardia. So, the test result of Valsalva maneuver ratio may reflect the, integrity of both divisions of the autonomic nervous system. The heart rate response in diabetics to Valsalva maneuver was concordant to those reported by other investigators'F'!". Our results showed that the studied diabetics had abnormal heart rate response to standing-up (relative bradycardia at the 30th beat to relative tachycardia at the 15th beat after standing-up). Diabetics with CAD had a mean value of 30: 15 ratio significantly lower than the other two groups. These results agreed with those reported in other studies (20-,22). This reflex is due to the unloading of the baroreceptors?". This reflex can be blocked by atropine and propranololv", Loss of this reflex may be due to the loss of the sympathetic and parasympathetic response to standing-up with the unloading of the baroreceptors in diabetics. In the current study, the response of heart rate to lying down; expressed as the mean values of SL 1 and SL 2 , were significantly lower in diabetics with CAD in comparison to diabetics without CAD and control subjects. Lying down induces tachycardia at the first 5 beats due to the increase in the venous return. SL 1 is the ratio between the relative bradycardia in the standing position to the relative tachycardia at first 5 beats after lying down. SL2 is the ratio of the relative

68

bradycardia at 20-25 beats after lying down to the relative tachycardia at first 5 beats. SL 1 can be abolished by bilateral vagotomy. On the other hand, SL 2 is mediated by both divisions of the autonomic nervous system as the pharmacological studies proved(25,26). Thus, our results showed that both divisions of ANS were affected in the diabetic subjects. These findings were concordant to those of other investigators(4,25,27). The mean value of the drop in SBP Upon standing up was significantly greater in the diabetics with CAD than in diabetics without CAD and control subjects. The fall of pressure at the area of baroreceptors after standing-up elicits an immediate reflex which leads to a strong sympathetic discharge throughout the body aiming to minimize the decrease in the BP in the head and upper body(28). Our findings may reflect the failure of the sympathetic efferentto the splanchnic vessels, and the peripheral blood vessels in diabetics. The results declared the effect of diabetes mellitus on the integrity of the sympathetic division. Other studies also reported failure of this adjustment in the standing position among diabetics(29.30). The mean value of. the increase in DBP during the sustained handgrip was significantly lower in diabetics either with or without CAD in comparison to control group. The rise in BP and HR at the beginning of isometric muscle contraction is largely due to a decrease in vagal tone, although increased discharge of the cardiac sympathetic nerves plays some role(16). The DBP is usually used as it gives the best separation between the normal and the abnormal responses'P'. Similar findings were detected in other studies(7,32). Our data showed that CAD has a significant correlation with TBMI and absolute weight in diabetics. These findings have been previously reported by Neil et al(33). The association of obesity, in absence of


diabetes, to CAD was also reported by Valensi and his co-workers'>" who found affection of the cardio-autonomic reflex tests in the obese non-diabetic subjects. Also, Arone et al(35) studied the effect of weight gain and loss on the CAR results, and found that 10% increase or decrease in the initial body weight will concordantly affect the degree of CAD. The underlying mechanism through which obesity affects autonomic balance is not clear. However, it was reported that insulin resistance promotes sympathetic stimulation (36,37). Also, it is well known that obesity is generally associated with disturbance in glucose metabolism and insulin resistance (38) Glycosylated hemoglobin, as an indicator of deranged glucose metabolism'P', was assessed in the studied diabetic groups. A significant correlation was found between the level of glycosylated hemoglobin and the . degree of CAD as assessed by CAR tests. So, it could be concluded that the metabolic control is an important factor in the· pathogenesis of CAD. These results are concordant with those shown by several investigators(3o.36.40). It was claimed that hyperglycemia increases the activity of aldose reductase which leads to elevated sorbitol and fructose concentration. Consequently, the high sorbitol concentration leads to decrease in the concentration of myoinositol that is actively transported by sodium dependent energy consuming active transport mechanism. The low level of myoinositol results in abnormal phosphoinositides, leading to reduced membrane sodium-potassium ATPase activity (41). Since myoinositol transport is dependent on Na+-K+ ATPase activity, the intra-axonal Na will be accumulated. This could affect nerve impulse generation. Intra-axonal accumulation of Na" leads to axonal swelling and axonal dysfunction, namely the separation of the termination of the myelin lamellae from the axon. Abnormal glycosylation of axonal proteins has been demonstrated in In animals. experimental diabetes


proteins has been demonstrated In experimental diabetes in animals. Non-enzymatic glycosylation of walls of the vasa-nervora and of the endoneural connective tissue matrix could also be important'?'. In peripheral nerve of diabetic rats, both motor nerve and sensory nerve conduction velocities were found to be decreased after 8 weeks of diabetes. Nerve action potential amplitude was decreased by 37%, and peripheral nerve blood flow was reduced by 57 % after 24 weeks of diabetesv'". A significant correlation was detected between the age of diabetics and the degree of CAD detected by 4 out of the 7 tests used in the study; namely Ell HR ratio, S~ ratio, decrease in SBP on standing-up, and increase in DBP with handgrip. These findings generally conform to the results showed by others(43,44). The above studies showed that Ell ratio, standing up HR ratio, and BP tests were negatively affected by the aging process. On the other hand, Valsalva test mayor may not be affected by the subject age, and sustained handgrip had a better correlation to the muscle power than to age per se(~1,43,45,46). Most of the biological studies' denoted that aging affects cells and the systems made up of them, as well as tissue components'!". Duration of diabetes had a significant correlation with the degree of CAD detected by all the studied tests, except the change in HR with Valsalva and after standing-up. Schnell et al(47) and Nsimies et al.(48) showed the passive effect of the disease duration on all the test results. Other studies also reported that the duration rather than the type of diabetes has a passive effect on the CAR tests(24,49) . In conclusion, the current study demonstrated that the cardio-autonomic damage is common in diabetics. Objective diagnosis and assessment of its degree are easy with the development of several simple

69

cardio-autonomic reflex tests. Both divisions of ANS seem to be affected in a comparable degree. Correlation with possible risk factors revealed a generally consistent correlation of the degree of CAD with TBMI, glycosylated hemoglobin, absolute weight and duration of diabetes. Based on the above conclusions, we can recommend that, in order to avoid or delay the progression of CAD, the weight and metabolic status should be kept under strict control. Regular follow-up of weight, glycosylated hemoglobin and CAR tests could help in prophylaxis of CAD.

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M,

RV,

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and

Correspondence: Dr. Yasser El-Wazir Department of Physiology Faculty of Medicine Suez Canal University lsmailia, Egypt Telephone: (064)329448 E-mail: [email protected]

72


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