Diabetology
 
 
Significance of cardiovascular autonomic dysfunction
   
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 It is estimated that 40 million people in the USA have hypertension, 14 million have diabetes and 4 million suffer congestive heart failure. Since all three conditions are age-related, as the longevity in industrialised societies continues to improve, the overall burden of congestive heart failure, hypertension and diabetes increases. These major diseases of civilisation are characteristically associated with an increased sympathetic autonomic cardiovascular drive1.
   
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 Prevalence of diabetes mellitus in the general population is approx. 5-6%, with a considerably higher proportion of up to 20-25% in the elderly and with a higher prevalence in some ethnic minorities2.
   
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 It is estimated, that due to sedentary lifestyles and other modern living conditions, the prevalence of diabetes type 2 will substantially grow in the very near future. Studies show that even on manifestation of diabetes mellitus, in up to one third of patients there is an early stage of autonomic neuropathy detectable by testing of HRV3.
   
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 In diabetes mellitus, the degree of autonomic dysfunction is related to the severity and duration of the disease4-6. Reduction of HRV parameters seems not only to carry negative prognostic value, but also precedes the clinical expression of cardiovascular autonomic neuropathy (CAN)7.
   
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 An increased mortality risk is associated with further progression of CAN8. Severe CAN is associated with up to 50% mortality rate within 5 years observation9. As this impact of CAN on prognosis in diabetes was recognised, it became clear that the estimation of cardiac autonomic function should be routinely performed in diabetic patients.
 
Autonomic dysfunction and other late complications of diabetes
   
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 Cardiac autonomic neuropathy is closely associated with other late complications in diabetes as well as with an autonomic dysfunction found in other organs including e.g. skin, gastrointestinal tract, nephropathy and/or urogenital tract including erectile dysfunction10.
   
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 In type 1 patients with microproteinuria, a diminished HRV is predictive for further systemic diabetic late complications10-12. Severity of CAN correlates positively with more advanced nephropathy in type 1 diabetes13.
   
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 In type 2 diabetes with manifested autonomic dysfunction, essential hypertension acts synergistically to depress cardiac reflex vagal and sympathetic function14. An additional risk, related also to other aspects of metabolic syndrome such as obesity and hypertension, autonomic dysfunction accounts for up to a four-fold risk of cardiovascular death when compared with non-diabetic individuals15.
   
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 In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than silent myocardial ischemia16.
 
Type 2 Diabetes & Metabolic Syndrome / Central Obesity
   
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 HRV testing enables risk stratification in polymorbid patients with obesity17. Parasympathetic nervous system dysfunction has been identified as a risk factor in childhood obesity18.
   
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 Short-term HRV assessment allows quantification of intervention effects and encourages motivation for long-term co-operation in obese subjects. Weight reduction correlates with normalisation and improvement of HRV pattern19.
   
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 Prospective HRV studies are effective for individual long-term prognostics and risk assessment in patients with metabolic syndrome20.
 
It is reported that enhanced sympathetic drive, independent of the underlying conditions, greatly increases the risk of poor cardiovascular outcomes. Targeting the underlying autonomic imbalance in congestive heart failure, hypertension and diabetes may not only be pathophysiologically sound, but such an approach may also lead to better outcomes1.
 
Examples of other related applications
   
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 Thyroid hormone deficiency is reported to be associated with an increased sympathetic influence on the autonomic cardiovascular system. The changes in sympathetic function could be explained by a secondary adaptation to an altered cardiovascular responsiveness21.
   
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 Increased sympathetic drive in symptomatic menopausal women can be reduced after estrogen replacement therapy, thereby giving a potentially beneficial effect on the cardiovascular system22.
   
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 Disorders of the central and peripheral nervous system are also associated with autonomic dysfunction leading to abnormalities of HRV23.
   
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 Dysfunction of the autonomic nervous system is an underrecognised but important aspect of the aetiological and clinical manifestation of primary degenerative dysautonomias. Dysautonomia in degenerative disorders also affect respiration, genitourinary function and sleep24.
   
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 More than half of all patients with end stage renal disease have detectable autonomic neuropathy, which may be aetiologically linked to the build up of metabolic waste products25,26.
   
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 Metabolic derangement in chronic liver disease and/or hypoxia in chronic respiratory disease can also induce autonomic abnormalities leading to reduced HRV27,28.
   
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 Abnormal autonomic function tests are common in some other systemic diseases, such as in HIV infected individuals. It has been shown that it may be attributed to severe global autonomic dysfunction which is not related to heart disease29.
   
• Stroke patients with generally low HRV but predominantly high sympathetic tone are at greater risk of mortality30,31.
   
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 A progressive reduction in intra-individual HRV pattern occurs in patients in intensive therapy units who develop brain death. This phenomenon may help to identify candidates for organ donation32.
   
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 In diabetes, renal, hepatic or neurological disease, improvement in metabolic or neurological function is commonly associated with a return to a normal HRV pattern33,34.
   
• A similar effect was seen after physical training in individuals with autonomic dysfunction35,36.
 
Diagnostics
As the central autonomic network is an integral component of an internal regulation system essential for survival, any biological input results in a critical involvement of the whole regulatory autonomic system37 while even the smallest functional abnormality is detectable by testing HRV.
 
Reflex test battery (time-domain)
   
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 The battery of cardiovascular reflex tests as proposed by Ewing38 is an established diagnostic tool for CAN that analyses variations on heart rate and blood pressure in time-domain.
   
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 The VariaCardio® TF5 offers the test battery consisting of the deep breathing test, Valsalva manoeuvre and orthostatic test.
   
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 The reliable discrimination between no CAN and early involvement in diabetes requires the application of the whole Ewing battery39. Each test is scored and the generated total Ewing score gives the grade of autonomic dysfunction.
 
Spectral analysis of HRV(frequency-domain)
   
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 Analysis of HRV in the frequency (spectral) domain allows a more detailed assessment of autonomic function showing the effects of sympathetic and parasympathetic subsystems38.
   
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 The method is based on a standardised protocol, using a modified orthostatic load that activates both autonomic branches, so that even minimal dysfunction can be detected39.
   
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 The analysis of spectral parameters of HRV provides reliable discrimination among autonomic dysfunction subgroups40.
   
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 This diagnostic discrimination has been currently shown to be of extraordinary importance as early stages of cardiovascular denervation in diabetes, appears to be reversible41.
   
 
Therapeutic Interventions
   
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 Depending on the level of CAN, it is possible to reverse the condition by physiological and/or pharmacological interventions. Maintaining good metabolic control is a prerequisite for successful intervention.
   
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 Regular fasting for balancing the metabolic state, temporarily increases the vagal tone42 even over a relatively short time span.
   
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 A three-month regular endurance-training programme induces an increase of complex sympathetic and parasympathetic supply in diabetic subjects for those without CAN and with early stage of CAN43.
   
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 It is possible to address the metabolic rationale of diabetic autonomic neuropathy44 or consequences of CAN through pharmacological intervention45,46.
   
 
References/Diabetology:

1. Julius S, Valentini M: Consequences of the increased autonomic nervous drive in hypertension, heart failure and diabetes. Blood Press Suppl 1998; 7(3): 5-13.
2. Data on file
3. Ziegler D et al: Prevalence of cardiovascular autonomic dysfunction assessed by spectral analysis, vector analysis. Amd standard tests of heart rate variation and blood pressure responses at various stages of diabetic neuropathy. Diabet Med 1992; 9(9): 806-814.
4. American Diabetes Association. Diabetic Neuropathy. In: Clinical practice recommendations 1996. Diabetes Care 19; 1996 (Suppl.1): S67-S92.
5. The Writing Team for the DCCT / EDIC Research Group: Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287(19): 2563-9.
6. Ziegler D: Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev 1999; 7: 342-57.
7. Pagani M: Heart rate variability and autonomic diabetic neuropathy. Diabetes Nutr Metab 2000; 13(6): 341-6.
8. O'Brien IA et al: The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med, 79/290; 1991: 495-502
9. Ewing DJ et al: The natural history of diabetic autonomic neuropathy. Q J Med 193; 1980: 95-108.
10. Hecht MJ et al: Neuropathy is a major contributing factor to diabetic erectile dysfunction. Neurol Res 2001; 23(6): 651-654.

10. Molgaard H et al: Early recognition of autonomic dysfunction in microalbuminuria: significance for cardiovascular mortality in diabetes mellitus? Diabetologia 37; 1994: 788-96.
11. Poulsen PL et al: 24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients. Diabetologia 40; 1997: 718-725.
12. Meinhold JA et al: Low prevalence of cardiac autonomic neuropathy in Type 1 diabetic patients without nephropathy. Diabetic Med 2001; 18: 607-613.
13. Sundkvist G, Lilja B: Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care 1993; 16/5: 773-9.
14. Takahashi N et al: Effect of essential hypertension on cardiac autonomic function in type 2 diabetes patients. J Am Coll Cardiol 2001; 38: 232-237.
15. Stamler et al: Diabetes, other risk factors, and the 12-year cardiovascular mortality for men screened in the multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 434-44.
16. Valensi P et al: Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001; 24: 339-343.
17. Andersson B et al: Urinary albumin excretion and heart rate variability in obese women. Int J Obes Relat Metab Disord, 1998; 22(5):399-405.
18. Yakinci C et al: Autonomic nervous system functions in obese children. Brain Dev 2000; 22(3): 151-153.
19. Nakano Y et al: Calorie restriction reduced blood pressure in obesity hypertensives by improvement of autonomic nerve activity and insulin sensitivity. J Cardiovasc Pharmacol 2001; 38 (Suppl 1): S69-74.
20. Liao D et al: Multiple metabolic syndrome is associated with lower heart rate variability: The Atherosclerosis Risk in Communities Study. Diabetes Care 1998;21(12):2116-22.
21. Cacciatori V et al: Power spectral analysis of heart rate in hypothyroidism. Eur J Endocrinol 2000; 143(3): 327-333.
22. Rosano GM et al: Effect of estrogen replacement therapy on heart rate variability and heart rate in healthy postmenopausal women. Am J Cardiol 1997; 80(6): 815-7.
23. Birner P et al: Cardiac autonomic function in patients suffering from primary focal hyperhidrosis. Eur Neurol 2000; 44: 112-116.
24. Chaudhuri KR. Autonomic dysfunction in movement disorders. Curr Opin Neurol 2001; 14(4): 505-511.
25. Rockel A et al: Uraemic sympathetic neuropathy after haemodialysis and transplanting. Eur J Clin Invest 1979; 9: 23-27.
26. Vita G et al: Comparative analysis of autonomic and somatic dysfunction in chronic uraemia. Eur Neurol 1988; 28: 335-340.
27. Dillon Jf et al: Autonomic function in cirrhosis assessed by cardiovascular reflex tests and 24 hour heart rate variability. Am J
Gastroent 1994; 89: 1544-1547.
28. Watson JP et al: Autonomic dysfunction in patients with nocturnal hypoventilation in extrapulmonary restrictive disease. Eur Respir J 1999; 13: 1097-1102.
29. Neild PJ et al: Cardiac autonomic function in AIDS is not secondary to heart failure. Int J Cardiol 2000; 74: 133-137.
30. Rapenne T et al: Could heart rate variability analysis become an early predictor of imminent brain death? A pilot study. Anesth Analg 2000; 91: 329-336 .
31. Dillon JF et al: The correction of autonomic dysfunction in cirrhosis by captopril. J Hepatol 1997; 26: 331-335.
32. Burger AJ et al: Effect of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 1999; 84(6): 687-91.
33. European Heart Failure Training Group: Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. Eur Heart J 1998; 19(3): 466-75.
34. Malfatto G et al: Short and long term effects of exercise training on the tonic autonomic modulation of heart rate variability after myocardial infarction. Eur Heart J 1996;17(4): 532-8.
35. Benarroch EE: The central autonomic network: Functional organization, dysfunction, and perspective. Mayo Clin Proc 1993; 68(10): 988-1001.
36. Ewing DJ et al: Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. An Intern Med 1980; 92(Pt 2): 308-11.
37. Ewing DJ et al: The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8/5: 491-8.
38. Weston PJ et al: Evidence of defective cardiovascular regulation in insulin-dependent diabetic patients without clinical autonomic dysfunction. Diabetes Res Clin Pract 1998; 42/3: 141-148.
39. Hayano JI et al: Postural response of low-frequency component of heart rate variability is an increased risk for mortality in patients with coronary artery disease. Chest 2001; 120(6): 1942-1952.
40. Howorka K et al: Optimal parameters of short-term heart rate spectrogram for routine evaluation of diabetic cardiovascular autonomic neuropathy. J Auton Nerv Syst 1998; 69/2-3: 164-172.
41. Ziegler D: Clinical ascpects, diagnosis and therapy of diabetic neuropathy. Ther Umsch 1996; 53(12): 948-57.
42. Howorka K et al: Influence of fasting on heart rate variability in diabetic patients with different degrees of cardiovascular autonomic neuropathy. Diabetes Nutr Metab/Clin Exp 1997; 10: 288-295.
43. Howorka K et al: Effects of physical training on heart rate variability in diabetic patients with various degrees of cardiovascular autonomic neuropathy. Cardiovasc Res 1997; 34: 206-214.
44. Ziegler D et al: Effects of treatment with the antioxidant a-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: A 4-month randomized controlled multicenter trial (DEKAN study). Diabetes Care 1997; 20(3): 369-373.
45. Boulton AJM: Current and emerging treatments for the diabetic neuropathies. Diabetes Reviews 1999; 7(4): 379-386.
46. Vinik et al: Gastrointestinal, genitourinary, and neurovascular disturbances in diabetes. Diabetes Reviews 1999; 7(4): 358-378.
 
 
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