|Year : 2017 | Volume
| Issue : 3 | Page : 150-157
Evaluation of cardiovascular autonomic nervous functions in diabetics: Study in a rural teaching hospital
Ashutosh Pathak, Suresh Gupta, Sunil Kumar, Sachin Agrawal
Department of Medicine, Jawahar Lal Nehru Medical College, DMIMSU, Wardha, Maharashtra, India
|Date of Web Publication||1-Feb-2018|
Dr. Sunil Kumar
Department of Medicine, Jawahar Lal Nehru Medical College, DMIMSU, Wardha, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Cardiovascular autonomic neuropathy (CAN) is a least understood complication of diabetes which is often underdiagnosed. It causes resting tachycardia, orthostatic hypotension, and exercise intolerance and is associated with higher cardiovascular mortality in diabetic patients. This stresses the need of early diagnosis of CAN to prevent higher mortality rates. Materials and Methods: Fifty cases of diabetes mellitus with no clinical evidence of cardiac disease were subjected to cardiac autonomic function (CAF) tests according to Ewing's criteria which included heart rate (HR) variability during deep breathing, Valsalva maneuver ratio, HR response on standing, blood pressure (BP) response to standing, and BP response to sustained handgrip to find the prevalence of CAN. Results: In this study, among 100 patients (50 case and 50 control), we found CAN in 52%. Out of which, parasympathetic neuropathy was seen in 52% of cases, and sympathetic neuropathy was seen in 26% of cases. CAF tests of HR variability during deep breathing, Valsalva maneuver ratio, HR response to standing, BP response to standing, and BP response to sustained handgrip found abnormal response in 68%, 40%, 52%, 12%, and 14%, respectively. Diabetic retinopathy and nephropathy were significantly associated with CAN (P = 0.0001, S). Conclusion: Prevalence of CAN among diabetics was 52%, and parasympathetic CAF tests are more sensitive for the detection of CAN than sympathetic CAF tests. Development of CAN in diabetic patients may lead to increased morbidity; thence, they should be routinely evaluated for CAN using these bedside tests.
Keywords: Autonomic function test, cardiovascular, complication, diabetes mellitus, parasympathetic autonomic function test, sympathetic autonomic function test
|How to cite this article:|
Pathak A, Gupta S, Kumar S, Agrawal S. Evaluation of cardiovascular autonomic nervous functions in diabetics: Study in a rural teaching hospital. J Pract Cardiovasc Sci 2017;3:150-7
|How to cite this URL:|
Pathak A, Gupta S, Kumar S, Agrawal S. Evaluation of cardiovascular autonomic nervous functions in diabetics: Study in a rural teaching hospital. J Pract Cardiovasc Sci [serial online] 2017 [cited 2019 Apr 19];3:150-7. Available from: http://www.j-pcs.org/text.asp?2017/3/3/150/224485
| Introduction|| |
Diabetes mellitus (DM) is a chronic condition which is characterized by hyperglycemia precipitating due to complete (Type 1 DM) or partial (Type 2 DM) absence of the insulin hormone., At present, there are approximately 40.9 million patients with DM in India, and this number is expected to rise to about 69.9 million by the year 2025. It is true that India is the diabetes capital of the world with 41 million Indians suffering from diabetes, every fifth diabetic in the world is an Indian. Such high burdens of diabetes are more likely to be linked with an increase in associated complications (namely, cardiovascular diseases (CVDs), nephropathy, retinopathy, and neuropathy); all of which can result in morbidity, disability, and even mortality.,
Autonomic nervous system (ANS) dysfunction is one of the major complications of DM, and this is usually associated with poor prognosis.,
Diabetic cardiovascular autonomic neuropathy (DCAN) is one of the most common complications in patients suffering from DM, which causes abnormalities in the heart rate (HR) control as well as the central and peripheral vascular dynamics. Consequences of DCAN comprise of exercise intolerance, intraoperative cardiovascular burden, orthostatic hypotension, and myocardial ischemia. At present, there is no cure for either DCAN or DM, and for most of the cases, damage to nerves in DCAN is irreversible. In addition, one recent study has stated that if DCAN is detected early, proper treatments can be performed so that further worsening of nerves can be either minimized or reversed. The only hope for combating DCAN is to have timely recognition, from which the patients can receive an immediate and sufficient medical care to prevent further deterioration of nerve damage.
Moreover, such diagnostic approach should be noninvasive and convenient to patients, which will enable a long-term monitoring since the onset of DCAN in diabetic patients is unclear and highly variable. There is a need to develop noninvasive computational methodologies that can detect an early indication of DCAN, which will allow doctors to give patients prompt treatments to either minimize further deterioration or reverse the nerve damage.
In keeping with the recommendations of the American Diabetes Association (1992), five standard cardiovascular reflex tests are used to assess cardiovascular autonomic function. These include variations in HR during deep timed breathing, Valsalva maneuver and standing up to evaluate cardiac parasympathetic activity and blood pressure (BP) responses to standing up and sustained handgrip to evaluate sympathetic nervous activity. Although these methods are used commonly, they may be associated with difficulties in patient compliance, particularly those who are elderly. The tests may also lack the sensitivity to detect subtle changes. This may be due to procedural issues and to the fact that these tests have diverse afferent pathways while suggesting a common efferent pathway. Further, each of the tests does not exclusively reveal the damage caused to one or the other arm of the ANS.
There have only been a few Indian studies on ANS changes in diabetics., The current study thus aimed to evaluate cardiovascular autonomic activity by means of HR and BP variability in diabetics.
| Materials and Methods|| |
This prospective observational study was carried out in Acharya Binova Bhave Rural Hospital attached with Jawahar Lal Nehru Medical College, Wardha, Maharashtra, in rural central India, from October 2015 to August 2017, after approval by the Institutional Ethics Committee (DMIMS [DU]/IEC/2015–2016/1485).
In this study, 50 diagnosed cases of diabetes according to World Health Organization criteria and 50 age- and sex-matched controls were included. Seriously ill patients with DM, acute coronary syndrome, stroke, or admitted in Intensive Care Unit, taking beta blocker, antipsychotics, anticholinergic, and other drugs (which causes autonomic dysfunction) that can alter the results were excluded from the study. Peripheral vascular disease, pregnant women with gestational diabetes, presence of uncontrolled hypertension, urinary tract infection (all of which could have transient proteinuria), fever, cirrhosis of liver, chronic kidney disease were excluded from the study [Figure 1].
We had studied 50 diagnosed cases of diabetes and 50 age- and sex-matched controls during October 2015–August 2017. The sample size was calculated on the basis of prevalence of cardiac autonomic neuropathy 76% and the level of significance at 5%.
N = Z 2 α/2 × P× (1 − P)/d 2
P = Prevalence of cardiac neuropathy = 76%
L = Allowable error = 16% of P = 16% of 76 = 12.16
Z α/2 = Level of significance at 5% = 1.96
N = 1.96 × 1.96 × 76 × 24/(12.16 × 12.16) = 47.38.
Data were collected by personal interview using the structured proforma. The proforma included sections to collect social, demographic information, determine the presence of CVD risk factors, glycemic control, and presence of preventive therapy. Informed written consent in local language (Marathi) was taken, and participants were assured of the confidentiality.
Information on sociodemography
Time since diagnosis of diabetes; current medication; family history of diabetes or CVD; presence of cardiovascular risk factors such as age, gender, family history, and hypertension were stated. Patients were also screened for body mass index (BMI) and waist by hip ratio.
Body mass index
We used Asian BMI; first individual's weight in kilogram was measured which was divided by the square of height in meter of the subject. Individuals were divided according to their BMI as underweight (<18.5), normal (18.5–22.99), overweight (23–27.49), and obese (27.5 and above).
It was calculated as the ratio of hip measurement to waist. Clothing and other items were first cleared from the waist and hip area. The individual was then asked to stand upright with arms relaxed at the side, feet evenly spread apart at approximately shoulder width, and body weight evenly distributed. The waist measurement was made at the midpoint between the top of the iliac crest (upper edge of the main pelvic bone) and the lower margin of the last palpable rib in the midaxillary line (lowest point of the rib cage that can be located by touch along the side of the body). Once the location of the waist was determined, a stretch resistant tape is passed around the individual. It was wrapped snugly around the body but not to the point of depressing or pinching the underlying skin. To ensure that the abdominal muscles were relaxed, the individual was asked to take two or three consecutive natural breaths and the measurement is made at the end of the last natural expiration. Hip circumference was measured in a similar manner, with the tape being passed around the hips at the widest circumference of the buttocks. Normal range – (males – <0.9: Females – <0.85).
Blood pressure was measured using a mercury sphygmomanometer, a minimum of two times in every participant in a sitting position and the mean of the readings will be used for analysis. Participants were classified as normotensive, prehypertensive, and hypertensive as per the JNC - 7 criteria.
Twelve-lead electrocardiography (ECG) was recorded by a trained worker who had no knowledge of the study or study population (the trained person recording ECG was blinded as far as the study was concerned); electrocardiographs were recorded after a supine resting period of at least 20 min. Patients showing left ventricular hypertrophy by Sokolow-Lyon Index criteria on ECG were included in this study.,
The fasting blood sugar was determined by analyzing a sample of venous blood after asking the participants to fast overnight (at least 8 h). A individual's venous sample was taken from the antecubital vein and collected in sugar bulb containing sodium fluoride as an anticoagulant. This was done to prevent glycolysis and better separation of serum or plasma as soon as possible.
The fasting blood sugar will be estimated by glucose oxidase-peroxidase method by machine robonic semiautomatic chemical analyzer.
- Glucose (mg/dl) = optical density of test × 100/optical density of standard.
The random blood sugar was estimated by glucose oxidase and peroxidase method.
Post meal blood sugar (oral glucose tolerance test) was estimated after 2 h after a meal by glucose oxidase-peroxidase method.
Glycated hemoglobin (HbA1c) was measured by using high-performance liquid chromatography by boronate affinity test.
Ophthalmoscopy was done for diabetic retinopathy and seen for characteristic lesions (cotton wool spots, flame hemorrhages).
Urinary albumin – Urinary albumin was detected by urine dipstick test for proteinuria; it can give a rough estimate of albuminuria. This is because albumin is by far the dominant plasma protein, and bromophenol blue, the agent used in the dipstick, is specific to albumin.
Measurement of cardiac autonomic function
The cardiac autonomic function (CAF) was evaluated with cardiac autonomic analyzer (CAN win, Windows base cardiac autonomic neuropathy analysis system, version 1, Genesis Medical Systems). It analyzes both sympathetic and parasympathetic ANS. The system uses echocardiogram and automatic noninvasive BP to conduct a battery of six tests.
After the interview and the anthropometric measurements, the individual's BP and HR were recorded in comfortable sitting posture. They will be explained about the tests of CAF.
The tests were performed on subjects with minimal, loose clothing, in a quiet ambient room with dim lighting and room temperature of 24–26 uC.
Tests based on heart rate for assessing cardiovascular autonomic status (to test parasympathetic component)
Heart-rate response to deep breathing test
The individual was in a supine position with all ECG leads attached. After breathing normally for 2 min, the patient was asked to perform 6 maximum deep breathings in 1 min. Continuous ECG record was obtained. E:I ratio was obtained by the following:
Heart-rate response to Valsalva maneuver
The individual was in sitting position with all ECG leads attached. Each individual performed the Valsalva maneuver for 15 s by blowing against a closed glottis through a mouthpiece attached to a sphygmomanometer and maintain a pressure of 40 mm Hg for 15 s. Three trials were performed at intervals of 5 min. A continuous ECG was recorded 1 min before the maneuver (resting period), during the maneuver (strain period, 15 s.) and 1 min subsequent to the strain period. The Valsalva ratio was calculated as follows.,,
Immediate heart-rate response to standing
Each individual was asked to lie quietly for 3 min. He was then asked to stand up and remain motionless. A continuous ECG was recorded, and a point was marked on ECG paper to identify the point of standing. The 30:15 ratio was calculated by taking the ratio of the R-R interval at 30th beat and at 15th beat after standing.,,
Tests based on blood pressure for assessment of cardiovascular autonomic status (to test sympathetic component)
Hand grip test
It is BP response to static exercise. The individual was asked to apply pressure on a handgrip dynamometer for 1 min at 30% of maximal voluntary contraction and simultaneously the BP; by using sphygmomanometer, changes were observed. The difference between the diastolic BP (DBP) just before the release of contraction and before handgrip began was taken as a measure of the response.,,
Blood pressure response to standing
Measuring the patient's BP while he/she was lying down quietly and again when he/she stood up performed the test. The postural fall after 2 min in BP was taken as the difference between systolic BP (SBP) lying and the SBP standing.
The score obtained for parasympathetic component was based on [Table 1] and [Table 2]:
- Deep breathing test
- Valsalva maneuver
- Lying to standing.
The score obtained for sympathetic component was based on:
- Lying to standing test
- Handgrip test (HGT)
- Cold pressor test.
All India Institute of Medical Sciences Autonomic Function Test Laboratory categorize patients based on parasympathetic and sympathetic component [Table 3].
|Table 3: Based on All India Institute of Medical Sciences autonomic function test laboratory criteria-scoring for parasympathetic and sympathetic component separately|
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We have taken only abnormal and normal values  and considered borderline as normal, so according to criteria, persons having 2 or more abnormal HR-based test were considered to have cardiac autonomic neuropathy as well as parasympathetic neuropathy, and for sympathetic neuropathy, since cold pressor test was not performed, therefore we have taken at least one abnormal test results out of two BP-based test.
Statistical analysis was done using descriptive and inferential statistics using Chi-square test, and Z-test for single proportion and software used in the analysis were SPSS 20.0 (Armonk, NY: IBM Corp) version and GraphPad Prism 6.0 version and P < 0.05 is considered as level of significance.
| Results|| |
In our study, we have enrolled 50 cases and 50 cage- and sex-matched controls with mean age of cases 54.92 years (standard deviation [SD] ±12.15), and of controls, 53.82 years (SD ± 14.56). Out of 50 cases, 29 (58%) were male and 21 (42%) were females, and in controls, 31 (62%) were male and 19 (38%) were females. The mean weight of cases was 62.24 kg (SD ± 8.19) and in controls was 60.74 kg (SD ± 8.25). The mean BMI of cases was 24.82 kg/m2 (SD ± 3.14) and of controls was 23.48 kg/m2 (SD ± 2.83), which were statistically significant (0.027, S). The mean waist-hip ratio of cases was 0.87 (SD ± 0.04) and in controls was 0.85 (SD ± 0.03), which was statistically significant (0.029, S). The mean HbA1c of cases was 8.34 (SD ± 1.20) and of controls was 5.23 (SD ± 0.62), which was statistically significant. The mean random blood sugar, fasting, and postmeal blood sugar in cases were 176.62 mg/dl (SD ± 64.31), 130.30 mg/dl (SD ± 42.45), 180.34 mg/dl (SD ± 59.11) and in controls were113.68 mg/dl (SD ± 11.17), 106 mg/dl (SD ± 16.69), 161 mg/dl (SD ± 11.71), respectively, which were statistically significant (0.0001, S), (0.0001, S), and (0.030, S). Out of 50 cases, there were 28 (56%) cases in which urinary albumin was present, and this number was 4 (8%) in controls, which was statistically significant (0.0001, S). There were 12 (24%) cases that were hypertensive and 8 (16%) cases that had diabetic retinopathy on fundus examination. The mean HR of cases was 78.90 beats/min (SD ± 7.09), and in controls, 74.34 beats/min (SD ± 9.40), which was statistically significant (0.008, S). The mean DBP and SBP of cases was 81.88 mm of Hg (SD ± 7.47) and 126.48 mm of Hg (SD ± 9.51) and those in controls was 70.84 mm of Hg (SD ± 7.16) and 118.36 mm of Hg (SD ± 6.73), which was statistically significant (0.0001, S) [Table 4].
The maximum number of patients (50%) was in the age group 41–60 years, followed by age group >60 years (36%). Younger patients (18–40 years age group) constituted in insignificant portion (14%) of total patients in the study group [Table 5].
Regarding the various autonomic functions, HR response to deep breathing was the most sensitive test to determine autonomic neuropathy. It is abnormal in 34 (68%) patients and normal in 16 (32%) patients. This was followed by an abnormal HR response to standing (30.15 ratio), which was abnormal in 26 (52%) patients and normal in 24 (48%). The abnormal HGT was seen in 7 (14%) patients and normal in 43 (86%) cases. Valsalva ratio was abnormal in 20 (40%) patients and normal in 30 (60%) cases. The least sensitive test to detect autonomic neuropathy was postural hypotension. This was abnormal in 6 (12%) cases and normal in 44 (88%) cases [Table 6].
|Table 6: Distribution of abnormal cardiovascular autonomic tests in cases and controls|
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The results showed parasympathetic neuropathy (criterion: result of at least two of the 3 tests of parasympathetic function being abnormal) was seen in 26 (52%) cases, while sympathetic neuropathy (criterion: abnormal result in one of the tests of sympathetic function) was detected in 14 (28%) cases [Table 7]. The majority of patients (19 patients, i.e., 38%) had three or more abnormal cardiovascular reflexes [Table 8].
|Table 7: Distribution of sympathetic and parasympathetic cardiovascular autonomic neuropathy in cases and controls|
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|Table 8: Distribution of number of abnormal cardiovascular reflex test in cases and control|
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Albuminuria was detected in 28 (56%) cases [Table 9]. Of the 28 patients with albuminuria, 23 had cardiac neuropathy and albuminuria; the remaining five patients had albuminuria without any abnormal autonomic cardiovascular function testing. Statistical evaluation revealed that albuminuria is significantly associated (P < 0.0001) with CAN. Diabetic retinopathy was detected in patients (16%) [Table 9]. All of them had albuminuria and cardiac autonomic neuropathy (CAN). Statistical evaluation revealed retinopathy is significantly associated (P < 0.0001) with CAN [Table 10].
|Table 9: Distribution of cardiovascular autonomic neuropathy, nephropathy, retinopathy, and raised glycated hemoglobin in cases and control|
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|Table 10: Association of nephropathy, retinopathy with cardiac autonomic neuropathy in cases|
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In the present study, HbA1c was raised in 22 (84%) cases in which cardiac autonomic neuropathy was present, but it was observed that HbA1c was also raised in 20 (83.33%) cases in which CAN was absent so there was a positive correlation (Pearson's Correlation r = 0.14, P = 0.36, NS), but it was statistically nonsignificant (P = 0.90, NS) [Table 11].
|Table 11: Association of raised glycated hemoglobin (>7.0) with cardiac autonomic neuropathy in cases and controls|
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In the present study, as the duration of diabetes was increasing the number of CAN, nephropathy and retinopathy were also increasing and were statistically significant (0.001, S), but HbA1c is independent of the duration of the disease and was not associated with duration of the disease (0.87, NS)
|Table 12: Distribution of cardiac autonomic neuropathy, nephropathy, retinopathy, and raised glycated hemoglobin on the basis of duration of diabetes mellitus|
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| Discussion|| |
The main outcome variable in our study was CAN derived from E/I ratio (parasympathetic function), Valsalva ratio and response to standing 30:15 (sympathetic and parasympathetic function), postural hypotension, and BP response to sustained handgrip (sympathetic system).
In this study, CAN was found in 52% cases. Parasympathetic neuropathy was found in 52% cases and sympathetic neuropathy in 26% cases. A recent study in Jaipur done by Mehta et al. revealed the prevalence of CAN in 58% cases – all of them having parasympathetic neuropathy and sympathetic neuropathy in 20% cases. HR response to deep breathing was the most sensitive test, 68% in this study.
Albuminuria was noted in 56% of patients in our study. Albuminuria was also statistically significantly associated with CAN. Reports of Mehta et al.'s study also showed a similar pattern of albuminuria, i.e., 35% of the patients in their study group. This may be due to the fact that in our study, urine dipstick was used for the detection of albuminuria and in other studies they consider microalbuminuria.
Retinopathy (both background and preproliferative) was detected in 16% of the type 2 DM patients in the present study. Mehta et al. reported a similar pattern, i.e., around 7.5% of type 2 DM patients had retinopathy. All of the patients with retinopathy had cardiac neuropathy and microalbuminuria in the present study.
Raised HbA1c was found in 22 out of 26 patients with CAN and in 20 out of 24 patients without CAN. There is no statistical difference between these results. This suggests that poor short-term glucose control has no correlation with the prevalence of cardiac neuropathy. The probable explanation of this lack of correlation is – HbA1c reveals glucose control over the past 2–3 months. As diabetes, particularly type 2 DM, is a long duration metabolic disease, a single measurement of HbA1c fails to reveal the exact nature of glycemic control over the past few years, which is important for the development of neuropathy, retinopathy, and nephropathy. Other metabolic parameters may play an important role in the genesis of long-term microvascular complications of DM.
Due to small sample size, results cannot be applied to the general population. We did not include the patients with borderline test results and considered them in the normal group so cannot be commented whether the patient having early CAN. We have included the patients with positive urine albumin on the basis of urinary dipstick test. Therefore, this study overestimates patients having nephropathy, as we did not consider microalbuminuria.
| Conclusion|| |
Assessment of CAN status in diabetics is of great importance as silent myocardial infarction and cardiac pulmonary arrest during general anesthesia or surgery is encountered in the presence of severe cardiac autonomic dysfunction. CAN detection should be included as a routine in workup of patients with type 2 diabetes, whether symptomatic or not as it often uncovers autonomic neuropathy even in asymptomatic state. It is of crucial importance to pinpoint some high-risk cases with a probability of sudden cardiac death. We suggest that minimum 3 tests based on cardiovascular reflex, measurement of urine albumin excretion rate, glycosylated hemoglobin, and fundus examination should be carried out in all diabetic patients at least 2–3 times a year.
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Conflicts of interest
There are no conflicts of interest.
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