|Year : 2015 | Volume
| Issue : 1 | Page : 8-11
Cardiac Autonomic Neuropathy and QTc Interval in Type 2 Diabetes
Jayaprasad Narayana Pillai, Suresh Madhavan
Department of Cardiology, Government Medical College, Kottayam, Kerala, India
|Date of Web Publication||14-Mar-2015|
Jayaprasad Narayana Pillai
Department of Cardiology, Government Medical College, Kottayam - 686 008, Kerala
Source of Support: None, Conflict of Interest: None
Context: An association between cardiac autonomic neuropathy and QT interval prolongation was demonstrated in many studies and it may predispose to sudden death in diabetes mellitus. Aims: To find out the prevalence of cardiac autonomic neuropathy and its relation to QTc interval and QTc dispersion in type 2 diabetes. Settings and Design: Observational study. Materials and Methods: Fifty patients with type 2 diabetes mellitus of more than 5-years duration and 30 age- and sex-matched controls without any history of diabetes were selected. A battery of five autonomic function tests was done in all cases. Heart rate, QTc values, and QTc dispersion were measured and compared among patients with and without autonomic neuropathy and controls. Statistical analysis used: Students t test/Chi-square test. Results: Among the 50 patients in the study population, 21 (42%) had severe autonomic neuropathy and 12 (24%) had early autonomic neuropathy. Mean heart rate was significantly more in patients with autonomic neuropathy than those without neuropathy. Diabetics with autonomic neuropathy had significantly higher QTc mean and QTc max values compared to diabetics without autonomic neuropathy and controls. QTc dispersion was significantly more among patients with autonomic neuropathy compared to those without autonomic neuropathy and controls. Conclusions: Diabetic autonomic neuropathy is associated with increase in resting heart rate and prolongation of QTc intervals. QTc max was correlating with severity of autonomic neuropathy. QTc dispersion is significantly high in diabetes mellitus with autonomic neuropathy.
Keywords: Autonomic neuropathy, diabetes mellitus, QT interval
|How to cite this article:|
Pillai JN, Madhavan S. Cardiac Autonomic Neuropathy and QTc Interval in Type 2 Diabetes. Heart India 2015;3:8-11
| Introduction|| |
Autonomic neuropathy is a common and often distressing complication of diabetes mellitus. Diabetic cardiac autonomic neuropathy (CAN), a serious complication found in one-fourth of type 1 and one-third of type 2 diabetic patients, is associated with increased morbidity and mortality.  CAN is associated with a poor prognosis and may result in postural hypotension, exercise intolerance, enhanced intraoperative instability, and an increased incidence of silent myocardial infarction and ischemia.  Diabetics with cardiac autonomic neuropathy are more prone for sudden cardiac death probably due to silent myocardial ischemia or infarction or due to malignant ventricular arrhythmias.  An association between cardiac autonomic neuropathy and QT interval prolongation was demonstrated in many studies and it may predispose to sudden death in diabetes. , Increased QT dispersion was also suggested as a marker of diabetic autonomic neuropathy.  Most of the data regarding QT interval and diabetic CAN are in type 1 diabetes with only few studies in type 2 diabetes. ,, This study is aimed to find out the relation of corrected QT (QTc) interval and QTc dispersion with diabetic cardiac autonomic neuropathy in type 2 diabetes so that we can identify a subset of diabetic patients who are at high risk for sudden cardiac death.
| Materials and Methods|| |
The study population comprised 50 patients with type 2 diabetes mellitus of more than 5 years duration and 30 age- and sex-matched controls without any history of diabetes. Inclusion criteria include diabetes mellitus diagnosed according to World Health Organization (WHO) criteria and onset of diabetes after 30 years and duration more than or equal to 5 years. Those with history of hypertension, history or electrocardiography (ECG) evidence of coronary artery disease, stroke/transient ischemic attack (TIA), electrolyte imbalance like hypokalemia or hypocalcemia, history of heart failure, renal dysfunction, hypothyroidism, and drugs affecting autonomic tone or QT interval were excluded.
All the patients were evaluated by detailed history including classical symptoms of autonomic neuropathy, physical examination, and blood investigations. A battery of five autonomic function tests was done in all cases.  A score of 0-2 was assigned to each test.
1. Postural fall in systolic blood pressure (BP) - Systolic BP was measured when the patient is lying down and 2 minutes after standing.
A fall of more than 30 mm Hg is abnormal - Score 2
A fall of 10-29 mmHg is borderline - Score 1
A fall less than 10 mmHg - normal Score 0
2. Increase in diastolic pressure during hand grip - Hand grip is maintained at 30%maximum for 5 minutes. A rise in diastolic BP in the contralateral arm from the value obtained before the test is measured.
Rise >16 mmHg - Normal Score 0
11-15 mmHg - Borderline Score 1
<10 mm Hg - Abnormal Score-2
3. Heart rate response to Valsalva manoeuvre-The patient forcefully exhales in to a manometer after closing the nose to raise the pressure to 40 mmHg for 15 seconds. Ratio of longest RR interval shortly after the manoeuvre to the shortest RR interval during the manoeuvre is then measured. This is expressed as Valsalva ratio.
Value >1.21 - Normal score 0
Value 1.11-1.20 - Borderline score 1
Value ≤1.10 - Abnormal score 2
4. Deep breathing test-Patient lies supine and breathes 6 times per minute. The mean of the differences in maximum and minimum heart rate during each breathing cycle for three successive breathing cycles is taken to give the maximum minus minimum heart rate.
≥15 beats per minute - Normal Score 0
11-14 beats per minute - Borderline Score 1
≤10 beats per minute - Abnormal Score 2
5. Heart rate response to standing - The RR interval is measured at beats 15 and 30 after the patient stands. A 30:15 ratio is measured.
Value ≥1.04 - Normal Score 0
Value 1.01-1.03 - Borderline Score 1
Value ≤1.00 - Abnormal Score 2
Total score ranged from 0-10. Based on the score obtained from the test, patient group was divided in to three groups:
Group 1: Severe autonomic neuropathy - Score >5
Group 2: Early autonomic neuropathy - Score 2-4
Group 3: No autonomic neuropathy - Score 0-1
Thirty healthy controls were selected randomly from bystanders attending the hospital. Significant medical illness was ruled out by history, physical examination, and investigations.
A 12 lead ECG was taken after 10 minutes rest in all patients at 50 mm/second speed. RR interval, heart rate, QTc interval, and QTc dispersion were calculated from the ECG.
QTc (second) = QT (second)/√ RR (second)
QTc mean was calculated from the QTc intervals of all the leads
QTc dispersion was then calculated by the formula
QTc dispersion = QTc max (longest QTc) - QTc min (shortest QTc)
Comparisons of heart rate, QTc mean, QTc max, QTc min, QTc dispersion were made in various groups and controls and significance assessed by students t test. Relation between age, sex, and autonomic neuropathy were assessed by Chi-square test.
| Results|| |
Among the 50 patients in the study population, 21 (42%) had severe autonomic neuropathy and 12 (24%) had early autonomic neuropathy by the autonomic function tests described as above. There was no relation between age and autonomic neuropathy. Mean age in the autonomic neuropathy group was 55.2 ± 8.2 years and that in the diabetic group without autonomic neuropathy was 52.2 ± 7.2 years (P > 0.05, statistically not significant). Incidence of autonomic neuropathy was similar among males and females. Autonomic neuropathy was more common in diabetics with longer duration of illness. Mean duration after diagnosis of diabetes was 10.9 ± 4.1years in the autonomic neuropathy group and 8.1 ± 3 in the no autonomic neuropathy group (P < 0.05, statistically significant). Mean heart rate was significantly more in patients with autonomic neuropathy (79.1 ± 8.3 per minute) than those without neuropathy (75.3 ± 5.7 per minute).
Autonomic neuropathy and symptoms
Most common among symptoms of autonomic neuropathy were postural giddiness (48.5%) and erectile dysfunction (60% of males). [Table 1] shows prevalence various autonomic symptoms among patients with or without autonomic neuropathy.
Prevalence of other target organ complications were higher among patients with diabetic autonomic neuropathy [Table 2].
|Table 2: Relation between diabetic complications and autonomic neuropathy|
Click here to view
QTc interval and diabetic autonomic neuropathy
Values of QTc mean, QTc max, QTc min, and QTc dispersion among the different groups were as below [Table 3].
|Table 3: Relation between QTc interval and diabetic autonomic neuropathy|
Click here to view
Diabetics with autonomic neuropathy had significantly higher QTc mean and QTc max values compared to diabetics without autonomic neuropathy and controls (P < 0.01). There was no significant difference of values of QTc mean and QTc max between diabetics without autonomic neuropathy and controls (P > 0.05). QTc min values were not different among the three groups (P > 0.05). QTc dispersion was significantly more among patients with autonomic neuropathy compared to those without autonomic neuropathy and controls (56.2 ± 13 vs. 38.8 ± 7, and 30.5 ± 7, P < 0.01). QTc max values were significantly more among patients with severe autonomic neuropathy compared to early autonomic neuropathy (445 ± 25 vs. 428 ± 24, P < 0.05). QTc mean, QTc min, and QTc dispersion values were not significantly different among patients with severe vs. early autonomic neuropathy.
| Discussion|| |
Diabetic neuropathy is a very common chronic complication of diabetes mellitus and its incidence in many studies range from 10-90%. Prevalence of autonomic neuropathy detected using autonomic function tests varies from 40-60%.  The diagnosis of CAN is usually done based on the results of a battery of autonomic tests rather than one single test, and sympathetic and parasympathetic components of the autonomic nervous system can be assessed.  Tests to assess sympathetic system include resting heart rate, hand grip test, and postural BP measurement. Parasympathetic assessment includes resting heart rate, Valsalva ratio, breathing test, and heart rate ratio with standing.
In this study, 50 type 2 diabetic patients with more than 5 year history of diabetes were evaluated for evidence of autonomic neuropathy using cardiovascular reflex tests. Of the 50 patients, 34 (68%) patients had somatic neuropathy and 33 (66%) patients had autonomic neuropathy. Among 33 with autonomic neuropathy 12 (24%) had early and 21 (42%) had severe autonomic neuropathy. Prevalence of autonomic neuropathy was showing an increase in trend with age. None in the less than 40-year age-group had severe autonomic neuropathy while 63.6% in the 61-70 age-group had severe autonomic neuropathy. The difference in mean ages between the groups with and without autonomic neuropathy was not statistically significant in our study. Previous studies by Pfeifer et al., have shown an increase in prevalence of autonomic neuropathy with age.  Autonomic neuropathy was not showing any significant difference in prevalence among males and females. In this study, 68% of males and 62% of females had autonomic neuropathy. There is a significant increase in prevalence of autonomic neuropathy with increase in duration of diabetes.
Symptoms of autonomic neuropathy were specifically asked. It was found that incidence of symptoms was less than expected except for postural giddiness and impotence. Postural giddiness was present in 48.5% and erectile dysfunction in 60% of males. Symptoms like gastro paresis (9.1%), nocturnal diarrhoea (3%), and sweating abnormalities (6.1%) were rare. According to Vinik et al., the incidence of gastro paresis was about 25%, diarrhea about 20%, and erectile dysfunction about 50%.  Other chronic complications like nephropathy, neuropathy, and retinopathy were showing significant increase with autonomic neuropathy. According to Zeigler et al., autonomic neuropathy well correlates with presence of other diabetic complications.  Mean heart rate in the autonomic neuropathy group was significantly higher than the mean heart rate in the no neuropathy and control groups. Increase in resting heart rate is an indicator of parasympathetic dysfunction according to Ziegler D. In our study, 72% of patients with heart rate more than 80 per minute had autonomic neuropathy.
Prolongation of QT interval was noticed in diabetic autonomic neuropathy by many investigators. A 1992 consensus statement on autonomic testing portrayed Bazett's heart rate-QTc prolongation as a specific yet insensitive indicator of diabetic autonomic failure.  According to a meta-analysis of 17 studies the sensitivity and specificity of QTc prolongation (>441 ms) for autonomic failure were 28% and 86%, respectively. Although QTc prolongation is relatively accurate for men, accuracy may be even greater for young men at low QTc thresholds. 
In this study QTc mean and QTc max values were measured in the autonomic neuropathy group and compared with no autonomic neuropathy group and controls. QTc mean in the three groups were 416 msec, 395 msec, and 391 msec, respectively. The difference between autonomic neuropathy and no autonomic neuropathy group was statistically significant. Similarly, QTc max values were 439 msec, 418 msec, and 407 msec, respectively in the three groups. Difference between the groups were statistically significant. QTc max in the severe autonomic neuropathy group (445 msec) was significantly more than that in early neuropathy group (428 msec). In our study, 75% of severe autonomic neuropathy patients had QTc max more than 440 msec. In the study by Germandy G et al., the QTc intervals in definite autonomic neuropathy was 456, early-435, and without autonomic neuropathy-413. 
Diabetic patients with autonomic neuropathy showed an increase in QTc dispersion that correlates with cardiac adrenergic dysinnervation assessed by decreased myocardial metaiodobenzylguanidine (MIBG) uptake.  Increased QT dispersion was also demonstrated in diabetic patients during episodes of hypoglycaemia.  In this study, QTc dispersion in the diabetic autonomic neuropathy group was 56.2 vs. 38.8 msec in diabetics without autonomic neuropathy and 30.5 in the control group. The difference was statistically very significant. Normal QT dispersion is <50 msec. Eighty-six percent of the severe autonomic neuropathy group had QTc dispersion of more than 50 msec. Since all other factors which prolong QTc were ruled out in our study group, the prolonged QTc intervals in our group is most likely due to autonomic dysfunction.
Limitations of the study include lack of clinical follow-up data so that the influence of autonomic neuropathy on mortality including sudden cardiac death were not assessed. Another limitation is that ischemic heart disease was not ruled out by coronary angiography.
| Conclusion|| |
Autonomic neuropathy is highly prevalent in long-standing diabetics and prevalence increases with duration of diabetes. Most common symptoms of autonomic neuropathy were postural giddiness and impotence. Other complications of diabetes like nephropathy, retinopathy, and neuropathy were more common in those with autonomic neuropathy. Diabetic autonomic neuropathy is associated with increase in resting heart rate and prolongation of QTc intervals. QTc max was correlating with severity of autonomic neuropathy. QTc dispersion is significantly high in diabetes mellitus with autonomic neuropathy. QTc prolongation and increased QTc dispersion are useful parameters in identifying the high-risk group with cardiac autonomic neuropathy among diabetics.
| References|| |
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553-79.
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-97.
Kahn JK, Sisson JC, Vinik AI. Prediction of sudden cardiac death in diabetic autonomic neuropathy. J Nucl Med 1988;29:1605-6.
Sawicki PT, Dähne R, Bender R, Berger M. Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Diabetologia 1996;39:77-81.
Ewing DJ, Boland O, Neilson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia 1991;34:182-5.
Arildsen H, May O, Christiansen EH, Damsgaard EM. Increased QT dispersion in patients with insulin-dependent diabetes mellitus. Int J Cardiol 1999;71:235-42.
Sivieri R, Veglio M, Chinaglia A, Scaglione P, Cavallo-Perin P. Prevalence of QT prolongation in a type 1 diabetic population and its association with autonomic neuropathy. The Neuropathy Study Group of the Italian Society for the Study of Diabetes. Diabet Med 1993;10:920-4.
Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications: The EURODIAB IDDM Complications Study Group. Diabetologia 1999;42:68-75.
Takebayashi K, Aso Y, Sugita R, Takemura Y, Inukai T. Clinical usefulness of corrected QT intervals in diabetic autonomic neuropathy in patients with type 2 diabetes. Diabetes Metab 2002;28:127-32.
Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985;8:491-8.
Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW, et al
. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 1984;7:447-53.
Vinik AI, Erbas T. Recognizing and treating diabetic autonomic neuropathy. Cleve Clin J Med 2001;68:928-30, 932, 934-44.
Ziegler D. Diabetic cardiovascular autonomic neuropathy: Prognosis, diagnosis and treatment. Diabetes Metab Rev 1994;10:339-83.
Kahn R. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Autonomic nervous system testing. Diabetes Care 1992;5:1095-103.
Whitsel EA, Boyko EJ, Siscovick DS. Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: A meta-analysis. Diabetes Care 2000;23:241-7.
Jermendy G, Koltai MZ, Pogátsa G. QT interval prolongation in type 2 (non-insulin-dependent) diabetic patients with cardiac autonomic neuropathy. Acta Diabetol Lat 1990;27:295-301.
Shimabukuro M, Chibana T, Yoshida H, Nagamine F, Komiya I, Takasu N. Increased QT dispersion and cardiac adrenergic dysinnervation in diabetic patients with autonomic neuropathy. Am J Cardiol 1996;78:1057-9.
Landstedt-Hallin L, Englund A, Adamson U, Lins PE. Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med 1999;246:299-307.
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Modelling the relationship between continuously measured glucose and electrocardiographic data in adults with type 1 diabetes mellitus
| ||Beatrice Charamba,Aaron Liew,Eileen Coen,John Newell,Timothy O’Brien,William Wijns,Andrew J. Simpkin |
| ||Endocrinology, Diabetes & Metabolism. 2021; |
|[Pubmed] | [DOI]|
||Correlation of staging and risk factors with cardiovascular autonomic neuropathy in patients with type II diabetes mellitus
| ||Muhanad M. Dhumad,Farqad B. Hamdan,Mahmood S. Khudhair,Hisham Y. Al-Matubsi |
| ||Scientific Reports. 2021; 11(1) |
|[Pubmed] | [DOI]|