annexure 1 NEED FOR STUDY
Diabetes mellitus is a syndrome of chronic hyperglycemia due to relative insulin deficiency, resistance, or both.
It affects more than 120 million people world-wide, and it is estimated that it will affect 220 million by the year 2020. Based on current trends, >360 million individuals will have diabetes by the year 2030.
Autonomic dysfunction is common in diabetics but symptomatic autonomic neuropathy is not that common.
One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN).
CAN probably contributes to the poor prognosis of CHD and CHF in diabetes.
Presence of Cardiac Autonomic Neuropathy(CAN) is responsible for silent myocardial
infarction and sudden death in diabetics.
Diabetic neuropathy is one of the common complications of diabetes and specifically autonomic neuropathy can affect several systems2.
Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes.
It encompasses damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics.
DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications.
Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated3.
The autonomic function tests are now widely used for the assessment of autonomic
function.
These tests are non-invasive and do not require sophisticated equipment.
All that required is an electrocardiogram machine, Heart rate monitor and sphygmomanometer.
This highlights the importance of simple non-invasive tools like ECG and sphygmomanometer in diagnosing asymptomatic cardiac autonomic neuropathy.
Type 2 diabetic patients with abnormal CVR tests may have increased mortality, and those combined with postural hypotension have higher mortality than those without 4.
In 1980, for the first time, an association of prolonged QTc interval with cardiac autonomic neuropathy was given, thereby opening the possibility of a rapid objective method for detecting cardiac autonomic neuropathy. Further studies demonstrated an association of prolonged QTc interval with cardiac dysautonomia in diabetes mellitus5.
This study is performed to estimate the Prevalence of Cardiovascular Autonomic Neuropathy with relation to duration of diabetes in our hospital and to check the utility of corrected QT interval in diagnosing it.
Annexure 2 REVIEW OF LITERATURE
DIABETIC CARDIOMYOPATHY
Diabetic cardiomyopathy refers to the derangement in the myocardium in the absence of extramural coronary atherosclerosis.
Diabetic cardiomyopathy is a term used by clinicians to encompass the multifactorial
etiologies of diabetes-related left ventricular failure characterized by both systolic and diastolic function.
(5) The Framingham Heart Study showed that men with diabetes who have congestive heart failure were twice as common as their non-diabetic counterpart, and that females with diabetes had a fivefold increase, in the rate of congestive heart failure.
The spectrum of heart failure ranges from asymptomatic to overt systolic failure.
Diabetes complicated by hypertension represents a particularly high-risk group for the development of congestive heart failure. (6) Diastolic dysfunction is exceedingly common (>50 percent prevalence in some studies) and may be linked to diabetes without the presence of concomitant hypertension.
DIABETIC AUTONOMIC NEUROPATHY
Symptoms relating to autonomic involvement in diabetic patients have been recognized since the last century (7), but the frequency with which the autonomic system
is affected was first stressed by Jordan in 1936 and then by Rundles in 1945.
In a power spectral analysis of type 2 diabetic patients and control subjects, both pro-insulin and C peptide levels were associated with sympatho-vagal imbalance of autonomic nervous function (9), and recently it has been shown the autonomic nervous dysfunction may be an early finding in subjects with insulin resistance. (10)
The two population based studies, one in Oxford and other in Pittsburgh, recorded
mainly cardiovascular autonomic function tests.
In the Oxford Community Diabetes study (11), 202 type 2 diabetics were tested from a total of 402 diabetic patients in the community of 29,873.
One or more cardiac autonomic tests were abnormal in 15.8% of type 2 patients.
The Pittsburgh epidemiology of Diabetes Complications study (12) found orthostatic hypotension (drop in blood pressure >30 mm Hg) in 3.4% of patients, and the
most common symptom suggestive of autonomic dysfunction was unawareness of
hypoglycemia (26%). Other symptoms were uncommon (0-8%).
Multicenter clinic based studies such as EURODIABIDDM Complications Study
(13) found orthostatic hypotension in 5.9% and abnormal Heart Rate Variability in 19.3%
of patients.
Ziegler and colleagues (14) (DiaCAN) reported that, in an unselected cohort of type
2 diabetics, there were borderline cardiac autonomic abnormalities in 12.1% and definite
abnormalities in 22.1% of patients. It is also recognized that the autonomic function tests
can be abnormal at the time of diagnosis of diabetes.
ECG CHANGES IN DIABETICS
The QT interval in the ECG reflects the total duration of ventricular myocardial
depolarization and repolarization.
A role of autonomic neuropathy in duration of QT interval in diabetic patient has been proposed because the diabetic patient with autonomic dysfunction show longer QTc compared with those without autonomic dysfunction (43).
The men with impaired heart rate variability (an index of autonomic dysfunction) showed significantly higher QTc compared with men without these complications suggesting a role for autonomic dysfunction in QTc prolongation in men (43).
Diabetics have a prolonged PR interval and more leftward frontal QRS axis than their non diabetic counterparts (44).
There is no significant difference in QRS duration between diabetics and non diabetics.
There is an increase incidence of intraventricular conduction blocks in diabetic patients than that of normal (45).
Annexure 3 Aims and objectives :
To evaluate the prevalence of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes patients in our hospital.
2. To correlate the prevalence of Cardiovascular Autonomic Neuropathy with duration of diabetes.
3. To investigate the relationship between Cardiac Autonomic Neuropathy and QTc interval prolongation.
Annexure 4 materials and meathod
(4.1) Source of data :
The subjects will be patients with Type-1 and type-2 Diabetes Mellitus, selected from the diabetic out patient department in Dr. B.R. Ambedkar Medical College.
Annexure 4
(4.2) Meathod of collection of data:
A total of 100 patients satisfying all the inclusion and exclusion criteria will be enrolled for the study from the population of Type 2 Diabetes patients who attended the out patient clinics and Inpatients of DR. BR AMBEDKAR MEDICAL COLLEGE, BANGALORE.
Written consent will be taken.
The patients were grouped into three according to the duration of diabetes.
Autonomic neuropathy testing by simple bed side tests will be done in op department and medical ward using ECG monitor, Pulseoxymeter and BP apparatus for the same 150 patients.
Each groups will be compared with one another with the available statistical data.
STUDY DESIGN
A Cross-sectional study to evaluate the Prevalence of Cardiovascular Autonomic Neuropathy in Type 2 diabetes and correlate it with duration of Diabetes.
To investigate the relationship between cardiac autonomic dysfunction and corrected QT interval.
Annexure 4 (4.3) evaluation and investigation
Baseline haematological and biochemical laboratory investigations will be done in all patients.
The following 5 tests for detecting Cardiac Autonomic Neuropathy will be performed as described by Ewing et all
• RESTING HEART RATE
• (>100beats/min taken as abnormal)
• BLOOD PRESSURE FOR POSTURAL OR ORTHOSTATIC HYPOTENSION
• (B.P recorded in the supine posture and just after 2 mins of standing-a fall in systolic blood pressure>20mm hg and/or diastolic blood pressure >10mm hg are considered abnormal)
• HEART RATE RESPONSE TO VALSALVA MANOEUVRE
• (ECG is continuously monitored during the procedure and ratio of the longest RR interval during the release phase to the shortest RR interval during straining phase is calculated and a value<1.2 is considered abnormal)
• HEART RATE VARIABLITY ON DEEP BREATHING
• (ECG is recorded continuously while patient is taking breath at a regular rate of 6-12 breaths/min.A difference of in heart rate <15 beats/min between expiration and inspiration is taken as abnormal)
• DIASTOLIC BLOOD PRESSURE RESPONSE TO ISOMETRIC EXERCISE
• (Pt is asked to squeeze a small ball in his/her left hand for about 5 mins and an increase in diastolic blood pressure <15 mm hg is considered abnormal)
Autonomic function / PointsResting heart rate:
<100
100-110
>110 / 0
1
2
Postural hypotension :
Fall in systolic bp
a) <20
b) 20-30
c) >30 / 0
1
2
VALSALVA ratio:
Longest RR / shortest RR
a) >1.2
b) 1.2 to 1.1
c) <1.1 / 0
1
2
Increased diastolic BP during sustained hand grip :
a) >15 mm of hg
b) 10 to 15 mm of hg
c) <10 mm o hg / 0
1
2
Heart rate variability on deep breathing:
a) >15 beats/min
b) 10 to 15 beats/min
c) <10 beats/min / 0
1
2
For grading of cardiovascular autonomic function, results are classified into normal, borderline and abnormal (scores 0,1,2 respectively).
score ‘0’ or ‘1’ = normal,
score 2,3,4 = borderline and
score ≥5 = abnormal autonomic function.
Annexure 4 (4.4) Inclusion & Exclusion Criteria:
Exclusion Criteria
1) Age above 65 years
2) Documented ischaemic heart disease
3) Documented valvular or congenital heart disease
4) Hypertension
5) COPD
6) Uraemia
7) Parkinsonism
Patient on b blockers or b agonist.
Inclusion criteria:
· Type 2 diabetes already on treatment and newly diagnosed patients
Annexure 5 list of references:
1. Nihal T. Vasan S. Bhatt R: A practical approach to Diabetes Mellitus, 2007
2. Jayaram 13 M et al: Type 2 Diabetes Mellitus and its omplications: A preventive program, 2008
3. Vinik A I, Maser E R. Mitchell B D, Freeman R:Diabetic autonomic neuropathy. Diabetes Care 2003; 26:1553-1579
4. Then H S et al. Abnormal cardiovascular reflex tests are predictors of mortality in Type 2 diabetes. Diabetic Meclicine 2001; 18(4):268-273
5. Aaron I. Vinik and Dan Ziegler: Diabetic Cardiovascular Autonomic Neuropathy. Circulation 2007; 115:387-397.
6. Braunwald's Heart disease, 7th edition ELSEVIER Saunders
7. Jain A, Avendaro G. Dharamsey S. et al. Lelt ventricular diastolic dysfunction in hypertension and role of plasma glucose and insulin: comparison with diabetic heart. Circulation 1996; 93:1396-1402. [PMID: ^8641029]
8. Buzzard.: Illustrations of some less known forms of peripheral neuritis, especially alcoholic monoplegia and diabetic neuritis. BMJ 1:1419, 1890.
9. Toyry et al Circulation 1997
10. Vasomotor tone in diabetic neuropathy. Annuals of int Med. 17 P: 353-1972. 11. Neil, H. A., Thompson, A., Thorogard, m., et al.: Diabetes in the elderly: the Oxford Community Diabetes study. Diabet. Med. 6:608, 1989
12. Maser, R. et al.: Diabetic autonomic neuropathy and cardiovascular risk. Pittsburgh Epidemiology of Diabetes Complications Study III. Arch. Intem Med. 150: 1218, 1990.
13. Stephenson, J.M., et al: Microalbuminuria is not rare before 5 years of IDDM. EIJRODIAB IDDM Complications study Group and the WHO Multinational Study of vascular disease in Diabetes Study Group. J. Diabetes Complications 8:166, 1994.
14. Ziegler, D., et al: The epidemiology of diabetic neuropathy. DiaCAN Multicenter Study Group. Diabetic. Med. 10(suppl. 2):82S, 1993.
15. Toyry, J et al: occunence. predictors, and clinical significance of autonomic neuropathy in NIDDM: ten-year follow-up from the diagnosis. Diabetes 45:308, 1996.
16. Ziegler, d. Mayer, P., et al.: The natural history of somatosensory and autonomic nerve dysfunction in relation to glycemic control during the first 5 years after diagnosis of diabetes mellitus. Diabetologia 34:882, 1991.
17. Quadric R. Ponzani P., et al.: Changes in autonomic nervous function over a 5year period in non-insulin-dependent diabetic patients. Diabet. Med 10:916, 1993.
18. Mustonen, J., Uusitpa, M., et al.,: changes in autonomic nervous function during the 4-year follow-up in middle-aged diabetic and nondiabetie subjects initially free of coronary artery disease. J. Intern. Med. 241:227, 1997.
19. Margolis JR et al: Clinical features of unrecognized myocardial infarction in diabetic patients; silent and symptomatic; 18 years follow up American Journal of Cardiology 1973 page 1-7.
20. Ewing et al. The natural history of diabetic autonomic neuropathy QJ Med. 1980;
49:95- 1 08
21. Mohan V et al. Autonomic Neuropathy in NIDDM and fibrocalculus pancreatic diabetes in south India, Diabet Med 1996; 13: 1038-43.
22. Toyry J P et al. Occurance, Predictors and Clinical significance of Autonomic neuropathy in NIDDM. Ten year follow-up from the diagnosis.Diabetes. 1996 Mar ;45 (3):308- 15.
23. Pappachan J M et al. Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis Postgraduate Medical Journal 2008; 84:205-210.
24. Aaron I. Vinik and Dan Ziegler: Diabetic Cardiovascular Autonomic Neuropathy. Circulation 2007;115;387-397
25. Massin MM, Derkenne B. Tallsund M, Rocour-Brumioul D, Ernould C, Lebrethon MC, Bourguignon JP: Cardiac autonomic dysfunction in diabetic children. Diabetes Care 1999; 22:1845-1850.
26. Kahn J.K., Sisson J.C., Vinik A.I. (1988) J. Nucl. Med., 29, 1605-06.
27. A Pourmoghaddas^7 A Hekmatnia et al: The relationship between QTc interval and cardiac autonomic neuropathy in diabetes mellitus: Mol Cell Biochem (2003) 249: 125-8.
28. CP Mathur*, Deepak Gupta**, :QTc Prolongation in Diabetes Mellitus - An Indicator of Cardiac Autonomic Neuropathy :JIACM 2006; 7(2): 130-2
29. H Oka et al - diabetes mellitus proceedings at 14th international Federation page 1304(68-71).
30. Kannal et al- Diabetes and cardiovascular diseases, the Framingham Heart Study JAMA 241:2035.1975.
31. Negrusz-kawecki m et al.:Frequency of silent ischemic heart disease in patients with diabetes mellitus: Pol Merkuriusz Lek: 1997 Aug3 (14)53 :6
32. O'sullivan JJ,Conroy R. et al.: silent ischemia in diabetic men with autonomic neuropathy. British Heart Journal 1991; 66:313-15:
33. I. Domuschiev: Cardiac autonomic neuropathy and its correlation with retinapathy in type 2 Diabetics: Biotechnol. & Biotechnol. Eq. 19/2005/3