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Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 23-28

Spectrum of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: A North India perspective

Department of Internal Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission03-Dec-2021
Date of Decision02-Mar-2022
Date of Acceptance10-May-2022
Date of Web Publication29-Jun-2022

Correspondence Address:
Ravi Kant
Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, India, 249203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCDM.JCDM_17_21

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Background: Cardiac autonomic neuropathy (CAN) is a known complication in diabetes patients but often remain underdiagnosed because of lack of proper investigation and long asymptomatic period. The study aimed to assess the spectrum of cardiac autonomic neuropathy prevailing among type 2 diabetes mellitus patients visiting a tertiary care hospital. Materials and Methods: The study was conducted as an observational cross-sectional study among the type 2 diabetes patients visiting the diabetic clinic. A total of 60 participants were included in the study, including both males and females, over one month. A cardiac autonomic neuropathy system analyser, manufactured by the Diabetik Foot Care India Pvt Limited (DFCI), Chennai (CANS 504), was used to screen for cardiac autonomic neuropathy (CAN). Results: A total of 60 patients were enrolled in the study. The mean age of the participants was 55.72 ± 12.62 (Mean ± SD). 38 (63.3%) of the participants were male, and 22 (36.7%) were Female. Early CANS dysfunction was seen among 21 (35.0%), Moderate CANS dysfunction in 9 (15.0%) and definite CANS dysfunction in 29 (48.3%) patients and only one patient had normal CAN study. Conclusion: CAN is a common microvascular complication highly prevalent among diabetes patients and may remain asymptomatic until an advanced stage, so screening of type 2 diabetes patients must be done at the time of diagnosis.

Keywords: Autonomic neuropathy, cardiac autonomic function test, cardiovascular medicine, cardiovascular physiology, diabetes mellitus

How to cite this article:
Sethi PP, Jatteppanavar B, Kant R, Pathania M, Bairwa MC. Spectrum of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: A North India perspective. J Cardio Diabetes Metab Disord 2022;2:23-8

How to cite this URL:
Sethi PP, Jatteppanavar B, Kant R, Pathania M, Bairwa MC. Spectrum of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: A North India perspective. J Cardio Diabetes Metab Disord [serial online] 2022 [cited 2023 Oct 4];2:23-8. Available from: http://www.cardiodiabetic.org/text.asp?2022/2/1/23/349196

  Introduction Top

As per the world health organisation (WHO), About 422 million people worldwide have diabetes, the majority living in low-and middle-income countries. An incredible number of deaths are contributed by diabetes each year, accounting for 1.6 million deaths/ year.[1] From the international diabetes federation estimates in 2019, 1 in 6 adults with diabetes in the world come from India.[2] Cardiovascular disease being the leading cause of mortality and morbidity among diabetes patients, cardiac autonomic neuropathy contributes to a significant proportion. Based on previous studies, the prevalence of CAN is variable based on published studies and ranges from 2% to 91% in type I diabetes mellitus (T1DM) and 25% to 75% in type 2 diabetes (T2DM).[3],[4],[5]

Cardiac autonomic neuropathy (CAN) is a known complication in diabetes patients but often remain underdiagnosed because of lack of proper investigation and long asymptomatic period. The disease often runs a long course before becoming symptomatic, and however recent studies also report the presence of CAN among prediabetes individuals.[6],[7] Affected populations are lower than diagnosed diabetes mellitus individuals but outnumber those with impaired fasting glucose.[8] Pathogenesis of CAN is complex and multifactorial that ultimately lead to neuronal ischemia and neuronal death/dysfunction. The autonomic dysfunction may manifest in any form like resting tachycardia, exercise intolerance, silent myocardial infarction, and intraoperative cardiovascular liability.[9],[10] Identifying these debilitating conditions among diabetes mellitus individuals is of utmost importance. It can be delayed and prevented by lifestyle modification and strict glycemic control. It can be reversed if diagnosed soon after the disease onset.[10] The present study shows the spectrum of autonomic dysfunction among type 2 diabetes mellitus individuals.

  Materials and Methods Top

The study was a cross-sectional, observational study conducted in a tertiary care hospital in North India. The patients visiting the outpatient diabetic clinic, functioning in the department of internal medicine, were included. A total of 60 Type 2 Diabetes Mellitus patients were diagnosed with diabetes mellitus according to the American Diabetes Association criteria.[11] were enrolled in the study. Patients who had i) other diseases associated with autonomic dysfunction, like thyroid disease (hyperthyroidism/hypothyroidism), severe anaemia ii)any critical illness secondary to systemic diseases (pulmonary, renal, cardiovascular), iii) drugs affecting autonomic nervous system like beta-blockers, diuretics, anti-arrhythmic, vasodilator, sympathomimetics, iv) underlying Heart disease(rheumatic heart disease, coronary artery disease, heart failure),v) not willing to participate in the study were excluded. After getting approval from the institutional ethical committee, participants were given the study information sheet. All those who fulfilled the inclusion and exclusion criteria signed an informed consent form. All patients were advised to avoid coffee, alcohol, smoking, and strenuous exercise in the last 24 hours.

The cardiac autonomic function testing was performed with the CAN system analyser (CANS 504) manufactured by the Diabetik Foot Care India Pvt Limited (DFCI), Chennai. It analyses both sympathetic and parasympathetic autonomic nervous systems using the R-R variations during rest, deep breathing, standing and Valsalva manoeuvre, and blood pressure changes during standing and sustained handgrip guided by the computer software. The system uses an electrocardiogram (ECG) and automatic non-invasive blood pressure measurements to conduct a battery of six tests. Every patient was explained the procedure prior to testing, and then the tests were performed in a quiet ambient room with dim lighting and room temperature of 24–26°C. The following tests of the autonomic nervous system were performed in all patients:

Parasympathetic function

  1. Resting heart rate: A resting heart rate >100 beats per minute was considered abnormal.

  2. Heart rate variation during deep breathing: The subject was made to lie supine, and the patient was asked to breathe deeply at six breaths per minute (a rate that produces maximum variation in heart rate). During breathing, a continuous ECG recording was obtained. The expiration: inspiration (E: I) difference was calculated as the difference in breath per minute. E: I difference less than 11 as considered abnormal, and 11–14 were considered borderline, and >14 was considered a normal response.

  3. Heart rate response to standing (30:15 ratio): The patient was asked to lie supine quietly and then asked to stand up. A continuous ECG was recorded, and the 30:15 ratio was calculated by taking the R-R interval ratio at the 30th and 15th beats after standing. A 30:15 ratio <1.01 was considered abnormal, 1.01–1.03 as borderline and >1.03 was considered normal.

  4. Valsalva ratio: The patient was asked to blow into a mouthpiece connected to a manometer to keep the pressure up to 40 mmHg and maintain it for 15 s. At the same time, a continuous ECG recording was done. After 30 s ECG was monitored again for 15 s. The Valsalva ratio was calculated as the most prolonged R-R interval after release to the shortest R-R interval during the manoeuvre. This procedure was avoided in patients with proliferative retinopathy. A Valsalva ratio of <1.10 was considered abnormal, 1.10–1.20 was borderline, and >1.20 was normal.

Sympathetic function testing

  1. Blood pressure response to standing: Patients were asked to stand from the supine position and remain standing for 2 min. A decline in SBP by ≥20 mmHg was considered abnormal. According to the original Ewing’s criteria, fall >30 mmHg was considered abnormal, but the criteria were modified according to the current definition of orthostatic hypotension.[12]

  2. Blood pressure response to sustained handgrip: The subject was asked to apply pressure on a handgrip dynamometer with a dominant arm three times. The highest of three readings was called maximum voluntary contraction. The subject was instructed to maintain handgrip steadily at 30% of maximum contraction for as long as possible to a maximum of 5 min. Blood pressure was measured on a non-exercising arm at rest and the end of the grip. The normal response is a rise of DBP by >15 mmHg, whereas a response <11 mmHg was considered abnormal.

The results were then categorised into one of the four groups.[13]

  • Normal

  • Early CAN – One abnormal parasympathetic test

  • Moderate CAN – At least two abnormal parasympathetic tests

  • Definite CAN – Abnormality in both parasympathetic and sympathetic tests.

  • Statistical analysis

    All the data were checked for any missing values. Statistical analysis was done using the Statistical Package for social sciences (SPSS) Version 23 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY). Descriptive statistics were calculated, and data were shown as the mean or percentages.

      Results Top

    A total of 60 patients were enrolled in the study. The mean age of the participants was 55.72 ± 12.62 (Mean ± SD). There were Among 8 (13.3%), 30 (50.0%), and 22 (36.7%) participants in <40 Years, 40–60 Years, and >60 Years, respectively. 38 (63.3%) of the participants were male, and 22 (36.7%) were Female. There was no significant difference in the age distribution of male and female groups (P = 0.880).

    The data which is not normally distributed are represented in median (IQR) in [Table 1]. The resting median (IQR)Heart Rate (BPM) was 85.00 (76–94.5). 11(18.3%) of participants had grade 2 resting heart rate dysfunction. Only 18 participants could perform the Valsalva manoeuvre and no one had any dysfunction. Early CANS dysfunction was seen among 21 (35.0%), Moderate CANS dysfunction in 9 (15.0%) and definite CANS dysfunction in 29 (48.3%) patients and only one patient had standard CAN study [Figure 1]. Among all patients with CAN, Maximum dysfunction was observed in sympathetic response to handgrip (93%) followed by an abnormal 30:15 RR ratio (72%) as represented in [Figure 2].
    Table 1: Cardiac autonomic neuropathy among patients

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    Figure 1: severity of CAN dysfunction in study population

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    Figure 2: Distribution of CAN among study population

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    While correlating the CAN dysfunction with age, there was a weak negative correlation between the 30:15 RR Ratio and Age (Years), and this correlation was statistically significant (rho = -0.27, P = 0.038). For every 1 unit increase in Age (Years), the 30:15 RR Ratio decreases by 0.03 units [Figure 3]. There was a significant difference between males and females in terms of Heart Rate (Resting) (BPM) (W = 285.500, P = 0.043), with the median Heart Rate (Resting) (BPM) being highest in the Female group. There was a significant difference between the two groups regarding E-I Difference (W = 560.000, P = 0.030), with the median E-I difference being highest in the Gender: Male group. There was a significant difference between the male and female in terms of distribution of Parasympathetic Function (χ2 = 9.664, P = 0.008); however, there was no significant association between sympathetic dysfunction with gender (P = 0.206), and there was no significant difference between a grade of dysfunction of CAN among male and female) (P = 0.078) as depicted in [Figure 4].
    Figure 3: Correlation between 30:15 RR Ratio and Age (Years) (n = 60), The above scatterplot depicts the correlation between 30:15 RR Ratio and Age (Years). Individual points represent individual cases. The blue trendline represents the general trend of correlation between the two variables. The shaded grey area represents the 95% confidence interval of this trendline

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    Figure 4: Association between Gender and Resting heart rate (BPM), E:I difference, sympathetic function and parasympathetic function (n = 60)

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      Discussion Top

    In our study, 59 (98.3%) out of 60 had cardiac autonomic neuropathy. Though there was no significant difference between the prevalence of overall cardiac autonomic neuropathy and the grade of dysfunction of cardiac autonomic neuropathy among males and females, the parasympathetic dysfunction showed a significant difference among males and females. The prevalence of abnormal sympathetic dysfunction was more (93% abnormal hand grip response) than an abnormality in parasympathetic dysfunction (72%). In our study, Early CAN was present in 35%, moderate CAN in 15% and definite CAN in 48.3% of patients, significantly higher than the study done by Bhuyan et al.[14] In their study, the normal population without any CAN was 32% compared to 1.7% in our study, and severe CAN was found in 21% compared to 48.3% in our study. The significantly high number of definite CAN and prevalence of CAN (98.3%) in our study population represents a serious cardiovascular impairment in a study population of North India. Given, enrolment of patients from the outpatient clinic for CAN screening, no patient was suggested to have symptomatic cardiac dysfunction. However, the duration of diabetes and glycaemic control could have led to this high number of cases, which has not been considered in our study. The study also differs from our study in terms of more involvement of parasympathetic system (56% of abnormal I: E difference) in comparison to 38% in our study, whereas our study reported maximum sympathetic dysfunction in the form of abnormal handgrip in 93% in comparison to 19% abnormal handgrip. The patients in our study did not have abnormal Valsalva among those who performed, whereas 32% had an abnormal Valsalva ratio in the previous study. This could be due to the severe Valsalva dysfunction in other patients who could not perform the test, showing a falsely negative impression of absent abnormal Valsalva function.[14] Another study by Zafer A Arif et al. showed diabetic cardiac autonomic neuropathy in 36.7% of patients, which is also lower than the prevalence of CAN in our study.[15] Another study by Pillai JN et al. showed severe autonomic neuropathy in 21 (42%) and early autonomic neuropathy 12 (24%), which is comparable to our study.[15]

    Though a significant difference between males and females was noticed in terms of resting Heart Rate (P = 0.043), E-I Difference(P = 0.030), Parasympathetic Function (P = 0.008), the overall cardiac autonomic neuropathy was not significantly associated with gender which is supported by the previous study by Bhuyan, et al.[14] While correlating with age, 30:15 RR Ratio was found to be significantly associated with age (rho = -0.27, P = 0.038). For every 1 unit increase in Age (Years), the 30:15 RR Ratio decreases by 0.03. This suggests that increasing age is associated with increased cardiac autonomic neuropathy. The pathophysiology of CAN supports this.[9],[16]

    The pathogenesis of cardiac autonomic neuropathy is multifactorial and complex. The pathogenesis evolves around the complex interaction of genetic factors, autoimmunity and hyperglycaemia induced by several downstream pathways, ultimately leading to oxidative stress. Neuronal axons being rich in mitochondria, the increased oxidative stress makes the neuronal axon susceptible to oxidative injury.[9] TCF7L2 gene has been found to be associated with cardiac autonomic neuropathy as well as proliferative retinopathy.[17] DNTM gene in type 1 diabetes associated with cardiac autonomic neuropathy.[18] The natural history of diabetic cardiac autonomic neuropathy involves early length-dependent involvement of the longest autonomic nerve, the vagus nerve. Hence early in the disease, an attenuated parasympathetic response is seen with predominant sympathetic activation. As the disease progresses, the sympathetic nervous system also gets involved. This forms the basis of cardiac autonomic neuropathy testing by resting heart rate variability seen in the earliest in subclinical CAN, seen among prediabetes and at initial diagnosis. This is followed by resting tachycardia and reduced exercise tolerance during the early stages of CAN and later by postural hypotension in advanced CAN due to sympathetic denervation.[10] In our study, postural hypotension was seen in 35% of patients showing an advanced stage of CAN; however, the disease remained asymptomatic until a later stage.

    The presence of CAN in diabetic patients is the strongest risk factor for early mortality and morbidity.[13],[19] Several researchers have found the development of CAN in diabetes individuals both in T1DM and in T2DM. certain landmark trials like the European Epidemiology and Prevention of Diabetes (EURODIAB) study.[20] and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.[21] DCCT research group, DCCT/EDIC study.[22] have confirmed the association. Early diagnosis and effective management by strict glycemic control is the key to successful management and sometimes reversal of the pathogenesis. American diabetic association also recommends screening cardiac autonomic neuropathy in patients with type 2 diabetes at the time of diagnosis.[11]

      Conclusion Top

    Our study identified the prevalence of a very high proportion of CAN in type 2 diabetes mellitus irrespective of the disease duration and glycaemic control in asymptomatic patients. The study showed both sympathetic and parasympathetic dysfunction, suggesting advances CAN among the population.

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    Conflicts of interest

    There are no conflicts of interest.

      References Top

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    Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, et al; DCCT/EDIC Research Group. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: The diabetes control and complications trial/epidemiology of diabetes interventions and complications study (Dcct/Edic). Circulation 2009;119:2886-93.  Back to cited text no. 22


      [Figure 1], [Figure 2], [Figure 3], [Figure 4]

      [Table 1]


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