|Year : 2022 | Volume
| Issue : 1 | Page : 29-34
The association between diabetic retinopathy and cardiac autonomic neuropathy in patients with type 2 diabetes
Magda Shukry Mohammad1, Mona Mohamad Abdelsalam1, Nesma Ali Ibrahim1, Mai Mohamed Salah Eldin2
1 Department of Internal Medicine, Endocrinology and Metabolism Unite, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Endocrinology, National Institute of Diabetes and Endocrinology (NIDE), Cairo, Egypt
|Date of Submission||01-Apr-2022|
|Date of Decision||26-May-2022|
|Date of Acceptance||28-May-2022|
|Date of Web Publication||29-Jun-2022|
Nesma Ali Ibrahim
Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
Background: Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that strongly associated with increased risk of cardiovascular mortality. Aim: The aim of this study was to evaluate the association between diabetic retinopathy (DR) and early CAN in patients with type 2 diabetes (T2D). Materials and Methods: The study was conducted on 60 patients with T2D, divided into two groups; group I included 30 patients with T2D complicated with DR and group II included 30 patients with T2D not complicated with DR. All participants underwent a detailed medical history, examination and laboratory measurements including, hemoglobin A1c (HbA1c) and urinary albumin/creatinine ratio (UACR). CAN was determined based on the results of tilt-table test which was done to all study participants. Results: On comparing tilt table test positive results of group I and group II, the results showed a significant difference between both groups (P = 0.004), being higher in group I (43.33% of group I were tilt table test positive) than in group II (only 10% of the group were positive). In group I, on comparing patients with positive tilt table test (CAN) and those with negative tilt table test (without CAN) regarding fundus findings, the results showed that 69.23% of patients with positive tilt table test had proliferative diabetic retinopathy (PDR), and 30.77% had non-proliferative diabetic retinopathy (NPDR), while in patients with negative tilt table test, 17.65% had PDR, and 82.35% had NPDR, the odd‘s ratio was 10.5 (P = 0.007). Regression of determinants for the presence of cardiac autonomic neuropathy in patients with T2D showed that, the increased duration of diabetes (P = 0.010) and the increased level of UACR (P = 0.001) were significantly associated with CAN in type 2 diabetic patients. Conclusion: DR is a strong predictor for CAN. So, fundus photography may be an alternative to autonomic function testing where facilities for the latter test are unavailable.
Keywords: Cardiac autonomic neuropathy, diabetic retinopathy, type 2 diabetes
|How to cite this article:|
Mohammad MS, Abdelsalam MM, Ibrahim NA, Salah Eldin MM. The association between diabetic retinopathy and cardiac autonomic neuropathy in patients with type 2 diabetes. J Cardio Diabetes Metab Disord 2022;2:29-34
|How to cite this URL:|
Mohammad MS, Abdelsalam MM, Ibrahim NA, Salah Eldin MM. The association between diabetic retinopathy and cardiac autonomic neuropathy in patients with type 2 diabetes. J Cardio Diabetes Metab Disord [serial online] 2022 [cited 2022 Aug 8];2:29-34. Available from: http://www.cardiodiabetic.org/text.asp?2022/2/1/29/349198
| Introduction|| |
Cardiovascular disease (CVD) is one of the leading causes of mortality and morbidity in patients with diabetes mellitus (DM). Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus, which is strongly associated with increased risk of cardiovascular mortality.
The incidence of CAN has been reported to be 6% and 2% annually in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), respectively. The prevalence of CAN increased from 9% at the close of the DCCT study to 31% one year later. Similarly, the prevalence of CAN increased from 19.8% in patients with prediabetes to 32.2% in patients newly diagnosed with T2D, with higher prevalence reported in patients with T2D and longer diabetes duration.
Unfortunately, clinical symptoms of CAN appear late during the disease course, which makes the use of cardiovascular reflex tests critical for CAN diagnosis., However, the presence of symptoms suggestive of dysautonomia as syncope, postprandial hypotension, resting tachycardia, exercise intolerance, gastroparesis, diarrhea, urinary incontinence, and erectile dysfunction may suggest the presence of CAN and these patients should be investigated.
Microvascular complications share common mechanisms, and several studies have shown that microvascular complications predict CAN development. The aim of this study was to evaluate the association between diabetic retinopathy (DR) and early CAN in patients with T2D.
| Materials and Methods|| |
This case–control study was conducted at endocrinology outpatient clinic, faculty of medicine, Ain Shams University Hospitals. Sixty participants were enrolled in the study, they were divided into two groups; group I included 30 patients with T2D complicated with DR and group II included 30 patients with T2D not complicated with DR, who were matched for age and gender.
All included patients were diagnosed as T2D according to The American Diabetes Association diagnosis criteria (American Diabetes Association, 2020). Ocular examination, including slit-lamp biomicroscopy and ophthalmoscopy were performed for all patients. Retinopathy was determined through fundus photography by an experienced ophthalmologist who was blinded to the autonomic test results. DR was classified as one of the following three stages: stage 0: no apparent retinopathy (equivalent to the scale of Early Treatment of Diabetic Retinopathy Study [ETDRS] level 10); stage 1: non-proliferative diabetic retinopathy (NPDR; ETDRS level 20–55); and stage 2: proliferative diabetic retinopathy (PDR, ETDRS level >61).
Exclusion criteria were the following: presence of cardiac arrhythmia, heart blockage, clinical coronary artery disease, presence of thyroid disease, presence of hypo- or hyperglycaemia in the previous 24 hours, presence of acute illness, severe systemic disease, medication that affects the autonomic nervous system (anti-arrhythmic medication, antidepressants, antihistamine and sympathomimetic cough preparations), alcohol abuse, use of neurotoxic medication or malignant disease, history of diabetic ketoacidosis and other secondary causes of diabetes.
CAN was determined based on the results of tilt-table test. During the tilt-table test, the blood pressure (BP) and heart rate (HR) response to an orthostatic challenge is used to provide a measure of sympathetic function. Like the early response to active standing, the early cardiovascular response to head-up tilt is largely caused by blood volume redistribution to the lower extremities. However, tilt-table testing is more sensitive to such redistribution because there is minimal contraction of lower extremity muscles, thus, further reducing the amount of venous return. This test is used to assess orthostatic intolerance caused by sympathetic nervous system dysfunction and to uncover a predisposition to neurally mediated (vasovagal syncope).
All enrolled patients were subjected to complete history taking and clinical examination including; age, sex, duration of diabetes, use of medications as well as exclusion of other systems disorders (including ocular diseases). Body mass index (BMI) was calculated as body weight in kilograms divided by the square of height in meters. Systolic and diastolic blood pressure were measured with a mercury sphygmomanometer with the patient in the sitting position.
For measuring hemoglobin A1c (HbA1c) level, a venous blood specimen collected in EDTA was required. After centrifugation, the supernatant was injected into the HPLC system. The gradient separation via HPLC at 30°C lasted 5 min. The chromatograms were recorded by an UV-detector. The quantification was performed with the delivered blood calibrator; the concentration was calculated via integration of peak heights respectively.
Urine samples were collected in serialized urine containers and used to detect albuminuria, urinary albumin/creatinine ratio (UACR). Urine microalbumin was measured by radioimmunoassay using the DPC Coat A Count kit (Diagnostic Products Corp., Los Angeles, CA, USA). Urine creatinine was determined by the alkaline picrate method.
All participants underwent tilt-table test as follows
The patient lies supine on the tilt table. Beat-to-beat and oscillometric BP instruments are attached to each arm. ECG monitoring takes place throughout the test. A large waist belt is placed around patients to secure them in case of syncope or unexpected falls. Once the patient is comfortable, with feet resting on the footboard, a baseline BP is recorded for at least 3 min. The patient is then slowly tilted upright to an angle of 60° to 80°. During testing, the patient is asked to report any symptoms. Both BP and HR are recorded throughout tilt-table testing, after which the patient is returned to a horizontal supine position. BP and HR are monitored in the supine position until patients return to baseline.
A normal tilt-table test is one in which there are no symptoms, and only a modest fall in systolic BP. Orthostatic hypotension is defined as a decrease in systolic BP of greater than 20 mmHg, diastolic BP greater than 10 mmHg accompanied by symptoms of orthostatic intolerance. The pattern, the temporal characteristics, and the degree of changes that occur in both the BP and HR define the test abnormality (positive result).
Statistical evaluation was carried out by using SPSS program version 21.0 (SPSS Inc., Chicago, IL, USA). Numerical data were presented as mean ± standard deviation (SD) and categorical data were presented as number and percentage of total. Comparison between numeric variables was performed using student t-test, and chi-square test was used to compare categorical variables. Logistic regression analysis with the forward conditional method was used to identify the odds ratio (OR) of risk factor. Statistical significance was set at p < 0.05.
| Results|| |
There was no significant difference between the study groups regarding age, gender, BMI, systolic blood pressure, diastolic blood pressure, and basal heat rate. While, there was a high significant difference between both groups regarding duration of diabetes, HbA1c and UACR [Table 1].
|Table 1: Comparison between group I and group II regarding demographic and laboratory data as well as tilt table test results|
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On comparing tilt table test positive results of group I and group II, the results showed a significant difference between both groups (P = 0.004), being higher in group I (43.33% of group I were tilt table test positive) than in group II (only 10% of the group were positive) [Table 1] and [Figure 1].
In group I, on comparing patients with positive tilt table test (CAN) and those with negative tilt table test (without CAN) regarding fundus findings using chi-square test, the results showed that 69.23% of patients with positive tilt table test had PDR, and 30.77% had NPDR, while in patients with negative tilt table test, 17.65% had PDR, and 82.35% had NPDR, the odds ratio was 10.5 [confidence intervals (CI) 95% 1.89-58.36 (P = 0.007)] [Table 2].
|Table 2: Comparison between patients with negative tilt table test (without CAN) and patients with positive tilt table test (CAN) regarding fundus findings|
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Regression of determinants for the presence of CAN in patients with T2D showed that, the increased duration of diabetes (P = 0.010) and the increased level of UACR (P = 0.001) were significantly associated with CAN in type 2 diabetic patients [Table 3].
|Table 3: Regression analysis for determinants of the presence of cardiac autonomic neuropathy|
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| Discussion|| |
Diabetes-related microvascular complications have a significant impact on morbidity and mortality of diabetic patients., CAN is a common underdiagnosed complication of DM., At the early stages it can be subclinical and becomes clinically evident as the disease progresses.,
Identifying patients with CAN is important, as CAN is associated with increased mortality, CVD, chronic kidney disease (CKD), perioperative morbidity, and lower-limb complications. As such, these patients should receive appropriate follow up and preventive treatment to slow the progression of these complications.
Associations between CAN and other microangiopathic diabetic complications have been reported in previous studies. The importance of such finding has not been sufficiently stressed although the correlation between CAN and retinopathy has been mentioned in some reports.,,,,,
The present study was conducted on sixty patients with T2D, who were divided into two groups: group I included 30 patients with T2D complicated with DR and group II included 30 patients with T2D not complicated with DR. All patients underwent a detailed medical history and examination, as well as laboratory investigations including HbA1c and UACR. The presence of CAN was determined based on the results of tilt-table test which was done to all study participants.
Regarding tilt table test results, the presence of CAN was significantly higher (P = 0.004) in diabetic retinopathy group compared to group without retinopathy, being positive tilt table test in 43.33% of patients with retinopathy, while positive in 10% of patients without retinopathy. Moreover, the results showed that 69.23% of patients with positive tilt table test had PDR, and 30.77% had NPDR, while in patients with negative tilt table test, 17.65% had PDR, and 82.35% had NPDR, the odds ratio was 10.5 [CI95% 1.89- 58.36 (P = 0.007)].
This was consistent with the results of Schmid et al. who revealed that proliferative diabetic retinopathy is related to cardiovascular autonomic neuropathy in T2D. In addition, Huang et al. showed that DR was a significant predictive risk factor of the presence of CAN in patients with T2D, as the CAN group had a significantly higher stage of DR than did the non-CAN group (p < 0.001). Also, the statistical evaluation by Basu et al. revealed that retinopathy was significantly associated (P < 0.05) with CAN. And, Kramer et al. founded that, early autonomic dysfunction, assessed by heart rate changes related to exercise, was associated with DR.
The present study revealed a significant association between micro-albuminuria and CAN, as the UACR was higher in patients with positive tilt table test than those with negative tilt table test (P = 0.001), the odds ratio was 9.98 [CI 95% 2.42–41.37 (P = 0.00)].
The results are consistent with those of previous findings, Viswanathan et al. reported that presence of diabetic nephropathy is associated with higher prevalence and early onset of CAN in T2D, and Bilal et al. revealed that diabetic nephropathy was related to the severity of CAN. The strong correlation between UACR and autonomic function again supports the notion that microvasculopathy plays an important role in CAN.
The regression analysis of the present study showed that there was a significant association between CAN and diabetic retinopathy (P = 0.007) as well as duration of diabetes (P = 0.010). This was in agree with Moţăţăianu et al. who performed a logistic regression analysis to identify determinants of CAN in patients with T2D, the odds of CAN increased with retinopathy [CI 95% (3.03–84.73), P = 0.002]. In the same study the odds of CAN increased with diabetes duration in T2D [CI 95% 1.67 (1.42–1.92), P = 0.0001].
An association between CAN and specific microangiopathic diabetic complications had been reported many times. Likewise, significant correlations between CAN and retinopathy, particularly proliferative retinopathy, and an increase in the urinary albumin excretion rate were found here. The pathophysiology of diabetic retinopathy and neuropathy shares many of the same triggering mechanisms. Hyperglycemia induces several metabolic pathways, such as nonenzymatic glycosylation, formation of advanced glycosylation end products, polyol pathway, hexosamine pathway, activation of diacylglycerol and protein kinase C, and production of reactive oxygen species.,
One possible explanation is that autonomic dysfunction might be related to diabetic retinopathy pathogenesis through alterations in BP pattern. These data suggest that alterations in BP pattern are associated with autonomic dysfunction. Moreover, autonomic dysfunction may affect the autoregulation of retinal vessels, allowing an abnormal BP pattern or small elevations to have a deleterious impact on the retina. This suggests that autonomic neuropathy may contribute to the development of retinal neovascularization, so as retinal vessels have receptors of the sympatho-adrenal system. Loss of responsiveness of the retinal vessels to metabolic and hemodynamic stimuli could lead to uncontrolled retinal hyper or hypoperfusion. However, the association between CAN and proliferative retinopathy may not imply a causative relationship. It may only suggest that CAN is a risk indicator, a marker of processes that underlie both the development of autonomic neuropathy and proliferative retinopathy. The aldose-reductase pathway is involved in the development of diabetic neuropathy and may similarly be responsible for intracellular accumulation of sorbitol in retinal pericytes.
Emerging research has focused on the implication of chronic low-grade inflammation in pathogenetic mechanisms of diabetic retinopathy.,, Moreover, genetic and epigenetic regulations such as DNA methylation, family history, and prediabetic condition have emerged as predisposing factors in the development of macro- and microvascular diabetic complications.,,
| Conclusion|| |
According to our data, DR is a strong predictor for CAN. The results here corroborate such findings and suggest that fundus photography may be an alternative to autonomic function testing in hospitals where facilities for the latter test are unavailable.
We wish to express our gratitude to the department of ophthalmology and department of cardiology, Ain Shams University, for being abundantly helpful and offering invaluable assistance, support and guidance. Deepest gratitude is to the department of public health, Ain Shams University, for the invaluable consultations in biostatistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Serhiyenko VA, Serhiyenko AA Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes 2018;9:1-24.
Dimitropoulos G, Tahrani AA, Stevens MJ Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014;5:17-39.
Pop-Busui R, Braffett BH, Zinman B, Martin C, White NH, Herman WH, et al
; DCCT/EDIC Research Group. Cardiovascular autonomic neuropathy and cardiovascular outcomes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study. Diabetes Care 2017;40:94-100.
Dimova R, Tankova T, Guergueltcheva V, Tournev I, Chakarova N, Grozeva G, et al
. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. J Diabetes Complications 2017;31:537-43.
Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O’Brien PC, et al
. Autonomic symptoms and diabetic neuropathy: A population-based study. Diabetes Care 2004;27:2942-7.
Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, et al
; Diabetic Neuropathy Study Group of the Italian Society of Diabetology. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis 2011;21:69-78.
Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al
; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285-93.
Rolim LC, Sá JR, Chacra AR, Dib SA Diabetic cardiovascular autonomic neuropathy: Risk factors, clinical impact and early diagnosis. Arq Bras Cardiol 2008;90:e24-31.
American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2020. Diabetes Care 2020;43:S14-31.
Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, et al
; Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110: 1677-82.
Domingueti CP, Dusse LM, Carvalho Md, de Sousa LP, Gomes KB, Fernandes AP Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complications 2016;30:738-45.
National Diabetes Information Clearinghouse. DCCT and EDIC: The Diabetes Control and Complications Trial and Follow-up Study; 2008. Available from: https://www.niddk.nih.gov/about-niddk/researchareas/diabetes/dcct-edic-diabetescontrol-complications-trial-followup-study/Documents/DCCT-EDIC_508.pdf
. [Last accessed on 2017 Jul 19].
Balcıoğlu AS, Müderrisoğlu H Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes 2015;6:80-91.
Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al
; Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: Clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639-53.
Edwards JL, Vincent AM, Cheng HT, Feldman EL Diabetic neuropathy: Mechanisms to management. Pharmacol Ther 2008;120:1-34.
Vinik AI, Erbas T Diabetic autonomic neuropathy. Handb Clin Neurol 2013;117:279-94.
Schmid H, Schaan B, Cecconello F, Maestri T, Neumann C Proliferative diabetic retinopathy is related to cardiovascular autonomic neuropathy in non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1995;29:163-8.
Kempler P, Tesfaye S, Chaturvedi N, Stevens LK, Webb DJ, Eaton S, et al
; EURODIAB IDDM Complications Study Group. Autonomic neuropathy is associated with increased cardiovascular risk factors: The EURODIAB IDDM complications study. Diabet Med 2002;19:900-9.
Cohen JA, Jeffers BW, Faldut D, Marcoux M, Schrier RW Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM). Muscle Nerve 1998;21:72-80.
Huang CC, Lee JJ, Lin TK, Tsai NW, Huang CR, Chen SF, et al
. Diabetic retinopathy is strongly predictive of cardiovascular autonomic neuropathy in type 2 diabetes. J Diabetes Res 2016;2016:6090749.
Basu AK, Bandyopadhyay R, Chakrabarti S, Paul R, Santra S A study on the prevalence of cardiac autonomic neuropathy in type-2 diabetes in eastern India. J Indian Acad Clin Med 2010;11:190-4.
Kramer CK, Leitão CB, Azevedo MJ, Valiatti FB, Rodrigues TC, Canani LH, et al
. Diabetic retinopathy is associated with early autonomic dysfunction assessed by exercise-related heart rate changes. Braz J Med Biol Res 2008;41:1110-5.
Viswanathan V, Prasad D, Chamukuttan S, Ramachandran A High prevalence and early onset of cardiac autonomic neuropathy among south indian type 2 diabetic patients with nephropathy. Diabetes Res Clin Pract 2000;48:211-6.
Bilal N, Erdogan M, Ozbek M, Cetinkalp S, Karadeniz M, Ozgen AG, et al
. Increasing severity of cardiac autonomic neuropathy is associated with increasing prevalence of nephropathy, retinopathy, and peripheral neuropathy in turkish type 2 diabetics. J Diabetes Complications 2008;22:181-5.
Moţăţăianu A, Maier S, Bajko Z, Voidazan S, Bălaşa R, Stoian A Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients. BMC Neurol 2018;18:126.
Hosseini A, Abdollahi M Diabetic neuropathy and oxidative stress: Therapeutic perspectives. Oxid Med Cell Longev 2013;2013:168039.
Villarroel M, Ciudin A, Hernández C, Simó R Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes 2010;1:57-64.
Valensi P, Pariès J, Attali JR; French Group for Research and Study of Diabetic Neuropathy. Cardiac autonomic neuropathy in diabetic patients: Influence of diabetes duration, obesity, and microangiopathic complications––the French multicenter study. Metabolism 2003;52:815-20.
Tang J, Kern TS Inflammation in diabetic retinopathy. Prog Retin Eye Res 2011;30:343-58.
Urbančič M, Štunf Š, Milutinović Živin A, Petrovič D, GlobočnikPetrovič M Epiretinal membrane inflammatory cell density might reflect the activity of proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 2014;55:8576-82.
Semeraro F, Cancarini A, dell’Omo R, Rezzola S, Romano MR, Costagliola C Diabetic retinopathy: Vascular and inflammatory disease. J Diabetes Res 2015;2015:582060.
Agardh E, Lundstig A, Perfilyev A, Volkov P, Freiburghaus T, Lindholm E, et al
. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med 2015;13:182.
Huang YC, Lin JM, Lin HJ, Chen CC, Chen SY, Tsai CH, et al
. Genome-wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology 2011;118:642-8.
Ciccone MM, Scicchitano P, Cameli M, Cecere A, Cortese F, Dentamaro I, et al
. Endothelial function in pre-diabetes, diabetes and diabetic cardiomyopathy: A review. J Diabetes Metab 2014;5:364.
[Table 1], [Table 2], [Table 3]