Changes In Cardiac Autonomic Dysfunction Biology Essay

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Abstract: Cardiac autonomic function was assessed at baseline, 6 and 12 months in 104 newly diagnosed patients of type 2 diabetes.

Criteria for normalcy were, heart rate variation during deep breathing ≥ 15 beats/min, deep breathing expiratory to inspiratory R-R ratio and valsalva ratio ≥ 1.21, sustained hand grip test ≥ 16 mm of mercury, cold pressor test ≥ 10, BP response to standing ≥ 10 mm of mercury and 30:15 R-R ratio on standing ≥ 1.04. An abnormal test was defined as the above parameters being < 10 beats/min, < 1.21, < 1.21, ≤ 10 mm of mercury, < 10, ≥ 30 mm mercury and ≤ 1.0, respectively.

A borderline test was defined as heart rate variation during deep breathing 11-14, sustained hand grip test 11-15 mm of mercury, BP response to standing 11-29 mm of mercury and 30:15 R-R ratio on standing 1.01-1.03.

Parasympathetic and sympathetic dysfunctions were present in 58.25% and 74.75% of patients at baseline, 46.97% and 81.25% at 6 months and 38.3% and 68.09% at 12 months after diagnosis of diabetes, respectively.

Improvement in autonomic function was most marked in patients having both dysfunctions; and did not correlate statistically with improvement in plasma glucose, glycated haemoglobin and urinary protein. Improvement was more pronounced in younger age group.

Introduction: The prevalence of cardiac autonomic neuropathy has been found to be higher in diabetics compared to healthy non diabetic controls (1-5). It has been reported that among recently detected type 2 diabetes, parasympathetic dysfunction was found in 44.2% and sympathetic dysfunction in 51.9% diabetics as against 11.9% and 22.1%, respectively among non-diabetic healthy controls(1). Cardiac autonomic neuropathy in diabetics increases mortality and morbidity (2-6). Therefore it is worthwhile to investigate whether cardiac autonomic neuropathy is reversible and if so, what factors help in its reversal or prevent its progression.

The aim of the present study was to assess the progression of cardiac autonomic neuropathy at 6 and 12 months after diagnosis among newly diagnosed diabetics; and the factors associated with such change.

Patients and Methods: In a hospital based cohort study, consecutive patients of diabetes mellitus diagnosed in the past one year during the period June 2006 to December 2007 were investigated and followed up. Patients did not have any history of ketoacidosis and urine ketones.

The Institute Ethics Committee approved the study and informed consent obtained from all participating subjects. All patients underwent a fundus examination before the autonomic function tests and patients with diabetic retinopathy, degenerative retinopathy and papilloedema were excluded. Patients having coronary artery disease, severe hypertension and pregnancy were also excluded.

Diabetes was diagnosed based on blood sugar reports (ADA 2006 diagnostic criteria). All patients were subjected to detailed history and clinical examination. All patients underwent a standard battery of tests to assess autonomic function (7). Patients were told not to have coffee or tea for 2 hours prior to the test.

Assessment of cardiovascular autonomic reactivity:

Deep Breathing Test: A baseline recording of ECG and respiration was taken for 30 seconds. Subjects were asked to sit quietly and were instructed to breath smoothly, slowly and deeply at 6 breaths /min (5 second inspiration and 5 second expiration) a rate which produces maximum variation in heart rate. After that deep breathing test was started and recording of respiration and ECG was continued throughout the test. Maximum and minimum heart rates during each breathing cycle were measured. Delta heart rate was the difference between the maximal and minimal heart rate during inspiration and expiration respectively, averaged for 6 cycles. E:I (expiratory to inspiratory) ratio of the longest R-R interval and shortest R-R interval averaged over 6 cycles.

Valsalva maneuver: Subjects sat quietly and blew into a mouth piece attached to sphygmomanometer generating a pressure of 40 mm/Hg for 15 sec. At the end of 15 seconds the pressure was released and due care was taken to prevent deep breathing before and after the maneuver. The heart rate measured from ECG normally increases (maximum in phase -II) during the maneuver followed by a rebound bradycardia (maximum in phase IV) after the pressure is released. Valsalva ratio was calculated from longest RR interval during phase IV to shortest RR interval during phase II.

Sustained Handgrip test: After recording the baseline blood pressure, subjects were asked to grip the handgrip dynamometer using maximum force with their dominant hand for a few seconds. The value was noted down and the procedure was repeated thrice. The maximum value of the three readings was considered as their maximal voluntary contraction (MVC).

A mark was made on the dynamometer at 30% of MVC of the subject. Each patient was then instructed that he/she should maintain the sustained grip on the dynamometer up to mark for 4 minutes. After the subject had started the contraction, the blood pressure was measured on the contra-lateral arm at 1st, 2nd and 4th minute. It was calculated by subtracting the baseline diastolic from the highest diastolic BP during the test.

Cold pressor test: After recording the baseline BP, subjects were advised to immerse their hand up to the wrist in water at 10o Centigrade for 1 minute. Blood pressure was measured just before the hand was taken out of water. It was calculated by subtracting from the highest diastolic BP during the test to the baseline diastolic BP.

Lying to standing test: After 10 minutes of supine rest, patients were told to stand within three seconds and BP and heart rate were recorded at baseline and at 2nd minute. 30:15 ratio was calculated as the ratio between the longest RR interval at or around 30th beat and the shortest RR interval at or around 15th beat.

Criteria for Normal, borderline and abnormal values in tests of cardiovascular autonomic function (7):

More than or equal to 15 beats/minute variation in the heart rate during deep breathing was considered as normal; 11-14 beats/minute variation as borderline and < 10 beats/min variation as abnormal.

Deep breathing E:I ratio and Valsalva ratio of ≥ 1.21 were considered as normal and < 1.21 as abnormal.

Sustained hand grip of ≥ 16 mm/Hg was considered normal, 11-15 mm/Hg as borderline and ≤ 10 mm/Hg as abnormal (beats/min).

More than or equal to 10 beats/min of Cold pressor test was considered as normal while < 10 beats/min as abnormal.

BP response to standing ≤ 10 mm/Hg was considered normal, 11-29 borderline and ≥ 30 abnormal.

30:15 R-R ratio on standing ≥ 1.04 was considered normal, 1.01-1.03 borderline and ≤ 1.0 abnormal.

Valsalva ?

Criteria for labeling patients with autonomic dysfunction:

Patients were categorized as having abnormal parasympathetic system alone if any of the three tests, namely, deep breathing test, deep breathing E:I ratio and 30:15 R-R ratio on lying to standing were abnormal, while rest of the tests were normal. Similarly, a patient was categorized as having abnormal sympathetic system if any of the three tests - sustained hand grip test, cold pressure and lying to stand test was abnormal while the remaining tests were normal.

Patients were classified to have both sympathetic and parasympathetic system dysfunctions if i) valsalva ratio was abnormal, ii) any test of one system was abnormal and any test of the other was borderline or iii) an abnormal test of both the systems.

Patients were defined as borderline dysfunction group if both or any of sympathetic and parasympathetic systems showing borderline abnormality and all tests including valsalva ratio were normal.

All patients were prescribed oral hypoglycemic agents for glycemic and metabolic control and HBA1c. Lipid profile and cardiac autonomic function tests were assessed at baseline, 6 and 12 months follow up. The changes in cardiac autonomic function were assessed at baseline and at 6 months and 12 months follow-up.

Define improvement

Statistical analysis:

Statistical analysis was done using STATA version 9.2. for WINDOWS. Data were presented as mean ± SD. Mean of the different parameters of patients were compared using independent samples t test. Pearson's correlation was calculated to know the relationship between different variables. Difference was considered significant at a 2 tailed p value of ≤ 0.05. The variables which showed significant correlation were put on regression model analysis.

Results:

104 consecutive patients were enrolled out of which 66 (63.5%) could be followed up for 6 months and 47 (45.2%) for 12 months.

Clinical characteristics of patients at baseline:

The age of patients at enrolment ranged from 22 to 78 years with a mean of 44.92 ± 12.33 years. The BMI of patients ranged from 16.2 to 39.9 kg/m² with a mean of 25.53 ± 3.98 kg/m². Similarly the mean waist circumference was 84.4 ± 6.2 cm. The mean systolic BP and diastolic BP were 129.2 ± 16.3 mm/Hg and 80.7 ± 9.5 mm/Hg respectively. The mean fasting blood sugar (FBS), post-prandial blood sugar (PPBS) and HbA1c were 195.54 ± 70.0 mg/dl, 291.92 ± 91.87 mg/dl and 9.22 ± 1.8% respectively.

Table 1 shows how the changes in various biochemical parameters from baseline to 6 and 12 months. As can be seen, a significant overall declining trend in all the biochemical parameters was observed from baseline to 6 months and 12 months. For example, the average post prandial blood sugar level was 270.7 ± 80.1 mg/dl at the time of enrolment and the same was 171.9 ± 32.0 mg/dl and 164.2 ± 18.7 mg/dl at 6 months and 12 months respectively. Pair-wise comparisons between two time points indicated significant improvement from 6 months to 12 months only in fasting blood sugar and HbA1c.

The proportion of patients showing normal, borderline and abnormal for various autonomic function tests is shown in Table 2. The number of patients subjected to various tests varied from 77 to 104 at baseline; 64 to 100 at 6 months; and was on 47 for all tests at 12 months. Common abnormalities observed at the baseline itself were E:I ratio (51%), followed by hand grip test (32.0%) and HRV (28.0%). At 12 months, also the major abnormalities remained similar to those at baseline, namely E:I Ratio (36.2%) followed by hand grip test (27.7%). Abnormal result for drop in systolic blood pressure after standing for 2 minutes was observed only in 4.0% of cases at the baseline and also at 12 months (4.3%).

A general trend of improvement with a declining proportion of patients with abnormal test results was observed for various autonomic function tests, except for hand grip test and test for drop in systolic blood pressure after standing for 2 minutes. For example, the proportion of patients with abnormal result to HRV was 27.9% at baseline which came down to 21.2% at 6 months and to 14.9% at 12 months. No change could be observed in the proportion of patients with abnormal result for drop in systolic blood pressure after standing for 2 minutes.

The dysfunctions as seen by various tests and pooled into two categories as sympathetic and parasympathetic involvements are shown in Table 3. At baseline, 17% patients were normal, 47.3% had both sympathetic and parasympathetic abnormalities; and about 10% had borderline abnormalities. About 20% had sympathetic abnormalities alone while about 5% had parasympathetic alone. Thus, abnormalities of the sympathetic system seem to be more prevalent than parasympathetic abnormalities (67.1% vs 52.7%) among the diabetic patients at the time enrolment, which continued at 6 months (64.7% vs 47.0%) and at 12 months (58.7% vs 39.1%).

A trend of declining number of patients with both sympathetic and parasympathetic abnormalities was observed from baseline to 12 months of follow-up. Similar trends observed in each type of autonomic dysfunctions, but the trend is more apparent in parasympathetic (52.7%, 47.0% and 39.1%) as compared to sympathetic dysfunctions (67.1%, 64.7% and 58.7%).

The changes in biochemical parameters from baseline to 6 months and baseline to 12 months are shown in the two groups of patients, namely, with improvement and with no improvement in cardiac autonomic functions are shown in Table 5. All the biochemical parameters showed reduced levels in the both groups, but the differences between the two groups were not statistically significant (P > 0.12) except for the serum triglycerides. Among those who improved the autonomic functions, the mean reduction of triglycerides from baseline to 12 months was 36.1 ± 73.3 as compared to an increase of 5.1 ± 72.6 (P = 0.04).

Discussion

The present study aimed to assess if autonomic dysfunctions revert in recently detected diabetics with good glycemic control (where are we talking about glycemic control?) and if so, what factors are associated with such reversal.

In the whole group of study patients at baseline, parasympathetic system dysfunction was found in 60 (3+57) out of 103 patients (58.25%) (Table-4), whereas sympathetic dysfunction was found in 74 (21+53) out of 99 (74.75%) (Table-4) patients.

In parasympathetic system, the most common abnormal test was deep breathing E:I ratio. In sympathetic system, increase BP during cold pressure test was the most common abnormal test.

Ziegler et al studied 130 newly diagnosed IDDM patients aged 12-40 years (took 120 healthy controls) in Germany and found out that among all tests of CAN, ≥3 of 6 tests positive in 7.7% patients & 0% controls, 2 of 6 tests positive in 9.2% patients & 1.7% controls.

Single autonomic dysfunction and borderline dysfunction were more prevalent in younger age groups (Table-4). Similar trend was observed when the patients were followed up to 6 months.

There was improvement in both FBS and PPBS at 6 and 12 months as compared to baseline P value<0.001(Table-1), but the mean difference of both FBS and PPBS at 6 months from baseline was more in 'AFT not improved' group than those of 'AFT improved' group and the difference was not significant, P-value=0.67 and 0.68 respectively (Table-5). At 12 months, mean difference for both FBS and PPBS was more in the 'AFT improved' group than those of 'AFT not improved' group though the association was not significant P-value=0.70 and 0.56 respectively (Table-5). Mean differences in HbA1c at 6 and 12 months from baseline were more in the 'AFT improved' group than those of 'AFT not improved' group though the association was not significant P-value=0.16 and 0.18 respectively (Table-5).

Similar findings were observed for serum total cholesterol (Table-5). The mean differences of triglyceride at 12 months from baseline in the 'AFT improved' group v/s 'AFT not improved' group and was statistically significant P-value < 0.05 (Table-14).

The mean difference between 6 months and baseline 24 hour urinary protein was higher in the 'AFT improved' group whereas it was lower in the 'AFT not improved' group at 12 months and both were not significant P-value=0.63 and 0.37 respectively (Table-15). 84(80.8%) out of 104 patients had microprotienuria and 17 (16.3%) patients had macroprotienuria at baseline. 61(92.42%) out of 66 patients had microprotienuria and 3 (4.55%) patients had macroprotienuria at 6 months. 43(91.49%) out of 47 patients had microprotienuria and only 2 (4.26%) patients had macroprotienuria at 12 months. Thus, there was an overall improvement in renal function as regards to protein excretion and this might be a reflection of improved glycemic profile during the follow-up period.

Overall assessment from the present study was that the improvement in autonomic function was most marked in the patients having both parasympathetic and sympathetic dysfunction at the baseline than other categories of dysfunction and the improvement in autonomic function was not correlated statistically with improvement in FBS, PPBS, HbA1c, 24 hour urinary protein excretion. Age of the patients seem to influence the changes in the autonomic function as the improvement was more pronounced in the younger age.

Table 1. Distribution of biochemical parameters of patient at baseline, 6 and 12 months

Variable

Pre

treatment

6 months

Post

treatment

12 months

Post

treatment

P

BL

Vs

6 m

BL

Vs

12 m

6 m

Vs

12 m

Overall

FBS

184.6 ± 69.4

118.5 ± 25.8

110.0 ± 17.3

< 0.001

< 0.001

< 0.05

< 0.001

PPBS

270.7 ± 80.1

171.9 ± 32.0

164.2 ± 18.7

< 0.001

< 0.001

0.11

< 0.001

HbA1c

8.98 ± 1.4

6.7 ± 1.0

6.4 ± 0.8

< 0.001

< 0.001

< 0.05

< 0.001

24 hour Uri. Protein

195.9 ± 231.0

145.3 ± 176.8

135.0 ± 148.5

< 0.05

< 0.05

0.45

< 0.001

24 hour Uri. Creatinine

890.8 ± 341.6

835.7 ± 229.6

797.9 ± 202.5

0.41

0.29

0.87

< 0.001

Cholesterol

197.6 ± 52.5

190.1 ± 29.9

184.4 ± 23.8

0.64

0.12

0.12

< 0.001

Triglycerides

180.0 ± 91.8

160.0 ± 45.0

155.2 ± 28.2

0.20

0.13

0.86

< 0.001Values are Mean ± SD

Table 2. Status of autonomic function tests at baseline, 6 and 12 months

Test

Baseline

6 Months

12 months

HRV

Baseline N = 104

6M N = 100

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

50.0

22.1

27.9

59.1

19.7

21.2

63.8

21.3

14.9

E:I Ratio

Baseline N = 104

6M N = 100

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

49.0

0.0

51.0

57.6

0.0

42.4

63.8

0.0

36.2

30:15 ratio

Baseline N = 104

6M N = 100

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

87.2

2.0

10.8

93.9

1.5

4.6

95.7

4.2

0.0

Valsalva Ratio

Baseline N = 77

6M N = 52

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

83.1

0.0

16.9

86.5

0.0

13.5

91.3

0.0

8.7

HGT

Baseline N = 103

6M N = 6

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

42.7

25.2

32.0

36.4

15.2

48.5

55.3

17.0

27.7

CPT

Baseline N = 102

6M N = 64

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

74.5

0.0

25.5

81.2

0.0

18.8

83.0

0.0

17.0

Drop in SBP after 2 minutes standing

Baseline N = 98

6M N = 66

12M N = 47

Normal (%)

Borderline (%)

Abnormal (%)

77.6

18.4

4.1

70.8

26.2

3.1

70.2

25.5

4.3

Table 3. Distribution of Sympathetic and Parasympathetic reactivity

Type of Dysfunction

Baseline

(N = 76)

6 months

(N = 51)

12 months

(N = 46)

No dysfunction

13 (17.1)

7 (13.7)

9 (19.6)

Parasympathetic alone

4 (5.3)

2 (3.9)

2 (4.3)

Sympathetic alone

15 (19.7)

11 (21.6)

11 (23.9)

Both dysfunctions

36 (47.4)

22 (43.1)

16 (34.8)

Borderline

8 (10.5)

9 (17.6)

8 (17.4)

Parasympathetic with or with out

Sympathetic dysfunction

40 (52.6)

24 (47.1)

18 (39.1)

Sympathetic with or with out

Parasympathetic dysfunction

51 (67.1)

33 (64.7)

27 (58.7)

Values in parentheses are percentages

Table 4. Age-wise distribution of abnormal autonomic cardiac function tests

Age group

(Years)

Baseline

No. (%)

6 months

No. (%)

12 months

No. (%)

P

< 40

25/32 (78.1)

22/26 (84.6)

16/22 (72.7)

40 - 49

22/27 (81.5)

9/11 (81.8)

10/12 (83.3)

≥ 50

16/17 (94.1)

13/14 (92.9)

11/12 (91.7)

P

< 0.05

0.31

0.41

Values in parentheses are percentages

Table 5. Distribution of changes in biochemical parameters with improvement status in cardiac autonomic functions

Parameter

Mean difference

P

Improved

Not improved

Reduction in Fasting blood sugar (mean ± SD)

BL to 6 months

BL to 12 months

60.8 ± 37.1

(N = 16)

68 ± 44.7

(N = 12)

68.8 ± 67.2

(N = 21)

61.2 ± 49.4

(N = 12)

0.67

0.70

Reduction in Post prandial blood sugar (mean ± SD)

BL to 6 months

BL to 12 months

94 ± 56.8

(N = xx)

106.9 ± 80.3

(N = XX)

105.1 ± 94.0

(N = xx)

90.9 ± 67.9

(N = XX)

0.68

0.56

Reduction in HbA1c (mean ± SD)

BL to 6 months

BL to 12 months

2.5 ± 1.0

(N = 16)

2.8 ± 1.5

(N = 12)

1.9 ± 1.4

(N = 20)

2.0 ± 1.3

(N = 18)

0.16

0.18

Reduction in Serum cholesterol (mean ± SD)

BL to 6 months

BL to 12 months

5.9 ± 22.5

(N = xx)

16.4 ± 52.8

(N = xx)

5.7 ± 22.5

(N = XX)

8.7 ± 31.2

(N = xx)

0.16

0.62

Reduction in Serum triglyceride (mean ± SD)

BL to 6 months

BL to 12 months

33.8 ± 55.8

(N = xx)

36.08±73.27

(N = xx)

8.3 ± 53.0

(N = xx)

-5.06±72.65

(N = xx)

0.12

0.04

Change in 24 hour urinary protein (mean ± SD)

BL to 6 months

BL to 12 months

69.2 ± 64.8

(N = xx)

71.2 ± 112.0

(N = xx)

61.8 ±79.2

(N = xx)

77.7 ± 96.5

(N = xx)

0.63

0.37

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