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The British Journal of Diabetes & Vascular Disease Review: Autonomic neuropathy: a marker of cardiovascular risk
British Journal of Diabetes & Vascular Disease 2003 3: 84 The online version of this article can be found at: can be found at:
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Autonomic neuropathy: a marker of cardiovascular risk Abstract
Cardiac autonomic neuropathy (CAN) represents a
serious complication as it carries an approximately
five-fold risk of mortality in patients with diabetes
just as in those with chronic liver diseases. The high
mortality rate may be related to silent myocardial
infarction, cardiac arrhythmias, cardiovascular and
cardiorespiratory instability and to other causes not yet
explained. Resting tachycardia due to parasympathetic
damage may represent one of the earliest signs. Typical
findings referring to autonomic dysfunction may
include exercise intolerance, orthostatic hypotension
and cardiac dysfunction to rest or exercise. Severe
autonomic neuropathy may be responsible for
spontaneous respiratory arrest and unexplained sudden
death. A relationship between the presence and/or
severity of CAN and corrected QT interval prolongation
is well documented. Better understanding of the
prognostic importance of autonomic neuropathy
followed the use of simple non-invasive cardiovascular
reflex tests. These most commonly include heart rate
rate, blood pressure (BP), myocardial contractility and as a con- variation in response to deep breathing, standing, the
sequence plays a pivotal role in the regulation of the cardio- Valsalva maneouvre and blood pressure response to
standing and sustained handgrip. Near normoglycaemia
The term ‘autonomic nervous system’ was coined by Langley is now generally accepted as the primary approach to
in 1898. Eichorst suggested in 1892 that persistent tachycardia the prevention of diabetic neuropathy, but is not
in diabetic patients might be due to damage to the vagus nerve.1 achievable in most patients. Our experience of the use
However, for many years autonomic nerve dysfunction was con- of the antioxidant alpha-lipoic acid in the treatment of
sidered an interesting but rare complication. A remark by the cardiac autonomic neuropathy is described.
obstetrician Timothy Wheeler to the diabetologist Peter J Br J Diabetes Vasc Dis 2003;3:84–90
Watkins in 1972 that loss of heart rate variation in the fetus inutero might be due to hypoxia of autonomic centers, sparked Key words: autonomic neuropathy, cardiovascular risk,
the thought of using a fetal heart rate monitor to assess whether QT interval, cardiovascular reflex tests, benfotiamin, beat to beat variability in heart rate was altered in diabetic patients with neuropathy.2 Subsequently, a significant decrease inbeat to beat heart rate variability was documented in two impor- Introduction
tant studies.3,4 Our better understanding of the clinical and prog- The autonomic nervous system, through the sympathetic and nostic importance of autonomic neuropathy was closely related parasympathetic pathways, supplies and influences every organ to the widespread use of simple non-invasive cardiovascular in the body. It closely integrates vital processes such as heart Just behind the centennial of the use of the term autonomic nervous system, we should ask whether autonomic disorders aresuitably investigated and managed in clinical practice. Correspondence to: Professor Peter KemplerI.Department of Medicine, Semmelweis University, 1083 Budapest, KorányiS.u. 2/a, Hungary.
Pathogenesis
Tel: +36 1 459 1500/1598; Fax: +36 1 313 0250 Both metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy, but their inter-relationships THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE Abbreviations
Trial acronyms
Alpha-Lipoic Acid in Diabetic Neuropathy study Autonomic Tone and Reflexes After Myocardial Infarction Deutsche Kardiale Autonome Neuropathie study United Kingdom Prospective Diabetes Study single photon-emission computed tomography naemia and hypertriglyceridaemia.12 Parasympathetic neuropa-thy in patients with type 2 diabetes has been reported to beassociated with obesity, microalbuminuria, hyperinsulinaemia are poorly understood.5 Vascular aetiology becomes more impor- and increased plasminogen activator inhibitor 1 activity.13 It has tant with age.6 Considerable evidence implicates nerve ischaemia been suggested that cardiac parasympathetic damage should be in the pathogenesis of reduced diabetic nerve conduction.
considered as a new component of the insulin resistance syn- Reduced endoneural blood flow and oxygen tension accompa- nied by increased vascular resistance have been demonstrated inexperimental studies early after the induction of diabetes.
Clinical presentation
Impaired blood flow and arteriovenous shunting in human dia- The autonomic nervous system, through the sympathetic and betic neuropathy have been shown by nerve photography and parasympathetic pathways, supplies and influences every organ in the body. It closely integrates vital processes such as heart rate, Metabolic changes include polyol pathway hyperactivity, BP, myocardial contractility and body temperature and conse- oxidative stress, increased advanced glycation and impaired quently plays a pivotal role in the regulation of the CV system.
essential fatty acid metabolism.5,6,8,9 These effects are exacerbat- Cardiac autonomic neuropathy (CAN) represents a serious com- ed by weakened trophic support. Hyperglycaemia has been plication. Survival patterns of patients with CAN compared to reported to decrease diacylglycerol and protein kinase C activity those without CAN are similar in diabetes mellitus and in chron- ic liver diseases. Meta-analysis of eight studies showed that mor- Nitric oxide may be the link between the metabolic and vas- tality after 5–8 years in diabetic patients with CAN was 29%, cular hypotheses of diabetic neuropathy.5 Early metabolic effects while it was 6% in those without CAN.15 Corresponding data of may decrease synthesis of nitric oxide in either the vascular the only four-year long follow-up study performed in patients endothelium or in the sympathetic ganglia leading to decreased with chronic liver diseases were 30% and 6%, respectively.16 nerve blood flow. Nitric oxide may also be involved in more distal Factors leading to increased mortality of CAN have not been def- defects of somatic nerve metabolism which impairs the activity of the nerve Na+, K+ ATPase by a mechanism involving phosphoinosi- Resting tachycardia due to parasympathetic damage may tide signalling and diacylglycerol. This may impair nerve conduc- represent one of the earliest signs of CAN. Experiences from tion velocity independently of ischaemia. It should be noted that large epidemiological studies indicate that tachycardia of any ori- neuropathies accompanying type 1 and type 2 diabetes are differ- gin is a major risk factor for cardiovascular and non-cardiovascu- ent. Aetiological factors other than hyperglycaemia seems to be lar death.17 The heart rate-mortality association is observed at any more important in patients with type 2 diabetes.10 age. The haemodynamic effects of faster ejection are indepen-dently conducive to vascular damage and to the development of Prevalence and risk factors
atherosclerosis. A practical implication is that tachycardia cannot Prevalence rates for autonomic neuropathy are difficult to ascer- be considered as an essentially benign condition and merely tain due to the different definitions of neuropathy and the vari- reflecting a temporary state of anxiety.17 able diagnostic procedures. The prevalence of autonomic neu- Dizziness, faintness, blackouts or visual impairment on stand- ropathy in the EURODIAB IDDM Complications Study was 36%.11 ing are clinical presentations of postural hypotension. Sometimes Significant correlations were observed between the presence of these symptoms may mistakenly be thought to represent hypo- autonomic neuropathy and age, duration of diabetes, HbA1C, presence of retinopathy, microalbuminuria, severe hypogly- CAN is associated with a high risk of unexpected and sudden caemia, ketoacidosis, cigarette smoking, lower high density death, possibly related to silent myocardial ischaemia/infarction, lipoprotein (HDL) cholesterol, total cholesterol/HDL cholesterol cardiac arrhythmias and hypoxia.15 Cardiorespiratory arrests dur- ratio, diastolic BP and fasting triglyceride.11 The study suggested ing or right after anaesthesia have been described. Any diabetic that autonomic neuropathy was associated with an increased patient with CAN is at a considerable anaesthetic risk. The mech- anisms by which CAN has been most frequently considered to Autonomic neuropathy in type 2 diabetes is associated with increase mortality include increased susceptibility to fatal ventric- an unfavourable metabolic risk profile including hyperinsuli- ular arrhythmias and increased propensity to CV events.18 A rela- tionship between the presence and/or severity of CAN and cor- nary artery disease is increased in diabetic patients.15 It is also rected QT (QTc) interval prolongation is well demonstrated in assumed that CAN is responsible for an altered perception of patients with either diabetes or chronic liver diseases,15,19-21 indi- myocardial ischaemia, painless myocardial ischaemia and silent cating that changes in QT interval appear to be due to auto- acute myocardial infarction (MI).15 However, the major draw- nomic impairment, rather than diabetes per se. QT-interval pro- back of most studies dealing with this topic is the lack of data longation predisposes the subject to cardiac arrhythmias and the on coronary morphology. In a recently published study, CAN risk of sudden death. It has been shown that QTc prolongation was independently associated with asymptomatic coronary correlated significantly with both parasympathetic and sympa- artery disease in patients with type 2 diabetes.31 In this study, thetic test results, indicating that besides the established role of planar scintigraphy and single photon-emission computed sympathetic dysfunction, even parasympathetic damage may tomography (SPECT) have been performed as well. The authors contribute to the development of QTc prolongation.20 Autonomic suggest that patients with CAN should be routinely screened for neuropathy should be taken into consideration when the aetiol- the presence of coronary artery disease, regardless of the pres- ogy of QT interval lengthening is not clear. Both CAN and QTc ence of symptoms. Silent MI should always be suspected in a prolongation may be present in patients with newly diagnosed diabetic patient with acute left ventricular failure (especially pul- type 1 diabetes.22 Studies must establish whether prolonged QTc monary oedema), collapse, vomiting and ketoacidosis. Although interval among these patients is reversible.22 the association between CAN and silent myocardial ischaemia, Cardiac dysfunction at rest or exercise may be associated is still discussed,32 data of a prospective study33 indicate that with CAN even in the absence of ischaemic heart disease.
event-free survival among diabetic patients with silent myocar- Impaired diastolic relaxation precedes the development dial ischaemia, just as in those without silent myocardial decreased ejection fraction due to systolic dysfunction.
ischaemia, is predicted by the presence of CAN. During the 4.5 Autonomic neuropathy may be associated with hyperten- years follow-up of this study a serious cardiovascular event was sion.23-25 Recently, we assessed CV autonomic function and 24- recorded in 50% of diabetic patients with CAN accompanied by hour BP profiles in patients with type 1 diabetes.26 The decrease silent myocardial ischaemia. Recently, diminished vasodilation of parasympathetic parameters (30/15 ratio and Valsalva ratio) capacity and reduced coronary blood flow has been reported in correlated significantly with systolic and diastolic hypertensive time indices as well as with systolic and diastolic hyperbaric On the other hand, the heart rate variability (HRV) decreases impact (mmHgxh) values. These data may suggest that a relative and its components alter their relative contribution in patients sympathetic hyperactivity due to predominant parasympathetic with coronary heart disease, acute MI, chronic heart failure and neuropathy might be responsible for hypertension.26 A similar hypertension. A large longitudinal observational study provided mechanism is supposed to have primary importance in the the first clinical evidence that decreased HRV was a powerful pre- pathogenesis of essential hypertension.
dictor of cardiac mortality after MI.34 The analysis of HRV in the The degree of loss of day–night rhythm of BP is associated frequency domain has also provided data of prognostic value; with the proportional nocturnal sympathetic predominance.
power spectral band calculated over 24 hours, particularly fre- Decreased BP fall combined with relative sympathetic predomi- quences below 0.04 Hz were strongly related to all-cause nance during the night might represent a risk factor for cardio- mortality and arrhythmic death independently of left ventricular vascular accidents and could modify the circadian pattern of car- ejection fraction.35 These studies showed that HRV was an inde- diovascular events in the diabetic population. As a consequence, pendent predictor of death additive to other post-infarction risk even normotensive diabetic patients are characterised by an variables, such as left ventricular ejection fraction and heart rate. increased left ventricular mass,27 which is an independent CV risk In recent years, more and more clinical attention has been factor. The ‘non-dipper’ phenomenon could be identified in both drawn to the key role played by the vagus nerve in the mediation normotensive and hypertensive diabetic patients with asympto- of HRV. The arrhythmogenic role of sympathetic hyperactivity is matic autonomic neuropathy.28 A reduction in the circadian heart firmly established and can be antagonised by vagal activation rate variability due to more frequent sleeping heart rates was and the ability to augment vagal activity can be quantified by the found in diabetic patients with CAN.29 Diminished circadian heart baroreflex sensitivity. The ATRAMI study provided clinical evi- rate variability as well as blunted or absent day–night BP varia- dence that after MI the analysis of baroreflex sensitivity has sig- tion should be considered as potential mechanisms leading to nificant prognostic value independent of left ventricular ejection acute ischaemic heart disease with specific diurnal pattern in fraction and ventricular arrhythmias and that it significantly adds patients with CAN.29 Recent data suggest that diminished systolic to the prognostic value of HRV.36 It has been shown more recent- and diastolic diurnal indices are associated with impaired BP ly, on analysing HRV and baroreflex sensitivity, that cardiovascu- response to standing in patients with type 1 diabetes.26 lar adaptation mechanisms in type 1 diabetic patients with long- Vascular instability, exercise intolerance, poor heat adaptation due to defective sympathetic thermoregulation, denervation As an important new finding, a highly significant correlation hypersensitivity and abnormal hormonal regulation may be pre- between CAN and cardiovascular disease has been shown by the EURODIAB IDDM Complications Study.11 Data indicate that silent The frequency of both symptomatic and asymptomatic coro- myocardial ischaemia in diabetic patients may result either from THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE Possible factors associated with high mortality and sudden Normal, borderline and abnormal values in tests of ● Silent myocardial ischaemia/infarction Borderline Abnormal
● Cardiorespiratory arrest/increased perioperative and peri-intubation risk Tests reflecting mainly
parasympathetic function
● Ventricular arrhythmias/prolongation of the QT interval ● Flattening of the nocturnal reduction of blood pressure and heart rate ● Exaggerated blood pressure responses with supine position and exercise ● Abnormal diastolic/systolic left ventricular function Tests reflecting mainly
● Impaired cardiovascular responsiveness sympathetic function
● Heat intolerance due to defective sympathetic thermoregulation ● Susceptibility to foot ulcers and amputations due to arteriovenous ● Increased risk of severe hypoglycaemia Data from the EURODIAB IDDM Complications Study con- CAN or from autonomic dysfuntion due to coronary artery dis- firmed that cardiovascular reflex tests rather than a questionnaire should be used for the diagnosis of autonomic neuropathy11 and To sum up, in a more direct or indirect way, many factors may indicate that the frequency of orthostatic hypotension is closely contribute to the poor prognosis of CAN in diabetic patients.
related to diagnostic criteria.42 According to different diagnostic Putative mechanisms are summarised in table 1. Nevertheless, criteria of abnormal BP response to standing (> 30 mmHg, > 20 other causes and mechanisms not explained yet might be of mmHg, and > 10 mmHg fall in systolic BP), the frequency of abnormal results was 5.9%, 18% and 32%, respectively. The fre-quency of feeling faint on standing in the same study was 18%, Diagnosis
thus, it was identical with the prevalence of abnormal BP Symptoms possibly reflecting autonomic neuropathy should not, response to standing when > 20 mmHg fall in systolic BP was by themselves be considered markers for its presence. Symptoms considered as abnormal.42 These results may indicate that a fall are important in the individual patients, however, they are diffi- > 20 mmHg in systolic BP after standing up seems to be the most cult to evaluate and quantitate as they are often nonspecific.26 reliable criterion for the assessment of orthostatic hypotension in Our better understanding of the clinical and prognostic impor- tance of CAN was closely related to the widespread use of sim- Measurement of heart rate response to deep breathing may ple non-invasive cardiovascular reflex tests. The most commonly allow evaluation of autonomic function in a simple, quick and used battery of non-invasive tests for assessment of cardiovascu- lar reflexes was proposed by Ewing and Clarke38 which included According to data from a recent meta-analysis, corrected QT- heart rate variation in response to deep breathing, standing and interval prolongation is a specific, albeit insensitive, indicator of Valsalva maneouvre, as well as BP responses to standing and sus- autonomic failure.43 Although QTc-prolongation is relatively accu- tained handgrip. These five tests are validated, reliable and repro- rate for men, accuracy may be even greater for young men at ducible, correlate with each other and with tests of peripheral low QTc thresholds.43 QTc interval alone should not be used for somatic nerve function and are of prognostic value.39,40 These the diagnosis of the severity of CAN.20 However, evaluation of tests still form the core of diagnosis of CAN. Normal, borderline QTc interval may provide a simple additional diagnostic aid to and abnormal values38,41 of the five standard cardiovascular reflex identify individuals with an increased CV risk.20 MI is the prime tests are summarised in table 2. Heart rate tests evaluating main- cause of death in type 2 diabetes. The prognostic importance of ly parasympathetic function appear to be abnormal more fre- QTc interval at discharge after MI has been proved. It should be quently and earlier in cardiac autonomic involvement, whereas noted that QT interval is influenced by many other factors includ- sympathetic damage assessed by BP tests usually occurs later and ing electrolyte abnormalities, myocardial ischaemia and alcohol is more often associated with clinical symptoms. toxicity. QT-interval measurement could be used as a screening test to select diabetic patients for more extensive cardiac investi-gations.44 Where the QTc interval is prolonged, further autonom-ic function tests should be performed together with further car- Key messages
diac investigations.22 Assessment of QT dispersion represents amore comprehensive diagnostic approach.44,45 Assessment of HRV represents a more sophisticated ● Cardiovascular autonomic neuropathy in diabetes carries method in the diagnosis of CAN. HRV is usually characterised in the time domain by simple statistical methods and in the fre- ● Silent myocardial infarction/ischaemia, resting quency domain by spectral analysis.37,45,46 Evaluation of barore- tachycardia and orthostatic hypotension are the most flex sensitivity provides a more focused measure of autonomic control.36,37 Scintigraphic assessment using 123I-metaiodobenzyl- ● Five standard tests of cardiovascular autonomic function guanidine (123I-MIBG) and SPECT are more sensitive in detecting CAN than conventional autonomic function tests.46,47 Using 123I- ● Glycaemic control is essential to prevent progression MIBG Schnell et al. has reported evidence of cardiac sympa-thetic denervation in newly diagnosed type 1 diabetic ● Alpha-lipoic acid is the most powerful agent for patients.47 It should be noted, however, that autonomic nerve dysfunction could be shown by standard CV reflex tests amongpatients with newly diagnosed type 1 and type 2 diabetes justas in those with gestational diabetes.48 According to the San Antonio Consensus Statement39 auto- hand, CAN evolves early in the course of diabetes even in the nomic neuropathy can be diagnosed when at least two of the absence of other microvascular complications. Neuropathy is a com- five standard tests are abnormal. However, reduced 123I-MIBG- mon complication even in patients with newly diagnosed type 2 uptake or decreased HRV even when all five tests are normal, should be considered as a sign of autonomic denervation.
Preferably, pathogenetically-based therapeutic strategies are recommended. It should be noted that peripheral neural Autonomic neuropathy and glycaemic control
damage has been the target of most clinical diabetic neuropa- The natural history of neuropathy is governed by the degree of thy studies. Experiences with aldose reductase inhibitors in glycaemic control. The unfavourable impact of long-term poor humans in general have been disappointing.15 Supplement- glycaemic control on the development and progression of CAN ation of the diet of diabetic subjects with gamma-linolenic acid is now generally accepted. In the light of evidence from prospec- failed to improve autonomic function.53 C peptide administered tive large-scale cohort studies, including the DCCT and the in physiological concentration as a three-hour long infusion UKPDS, tight glycaemic control is clearly a priority in primary and was found to influence CAN favourably in type 1 diabetic secondary prevention of neuropathy. A close relationship patients54 but whether this is sustained long term is not known.
between CAN and glycaemic control has been documented in Inhibition of advanced glycation end-products (AGEs) proved the EURODIAB IDDM Complications Study as well.11 Data sug- to be more effective with thiamine pyrophosphate and pirydox- gest that intensive diabetes therapy resulting in long-term HbA1C amin than aminoguanidine.55 The lipidsoluble derivate benfoti- levels of approximately 7% prevents the onset and slows the amine is characterised by five times higher bioavailability com- progression of neuropathy in type 1 and type 2 diabetic patients.
pared to the water soluble compound56 and was shown to be In the DCCT, intensive insulin therapy reduced the risk of devel- effective in the treatment of diabetic polyneuropathy.57 oping clinical neuropathy by 64% within five years in type 1 dia- Experiences from cardiology indicate that long-term increases in betic patients and intensive diabetes therapy was also able to heart rate variability and reduction in sudden cardiac death have slow the progression and development of abnormal autonomic only been shown with lipophilic agents that readily penetrate the function.49 Recently, the beneficial effect of tight glycaemic con- blood nerve/blood brain barrier.18 In accordance with these trol on myocardial sympathetic innervation assessed by 123I-MIBG observations experimental data indicate a preventive effect of scintigraphy was shown in a four-year prospective study in benfotiamine on the development of CAN.58 Alpha-lipoic acid (thioctic acid), a powerful free radical scav- enger improves nerve blood flow, reduces endoneurial hypoxia, Therapy of CAN
lipid peroxidation and oxidative stress.59 Improvement of insulin- Autonomic and sensory nerve dysfunction represent progressive stimulated glucose disposal was documented in patients with forms of neuropathies and are therefore of utmost clinical and type 2 diabetes after administration of thioctic acid.60 During prognostic importance.51,52 With that in mind, even a retarding treatment with alpha-lipoic acid in the ALADIN study, beneficial effect on autonomic function may have particular importance. Is effects upon symptomatic peripheral neuropathy were there a need for a specific treatment for CAN? The answer is observed.61 Improvement of cardiac autonomic function assessed undoubtedly yes. On the one hand, CAN is associated with poor by heart rate variability has also been documented in the DEKAN prognosis and carries a five-fold risk for mortality. On the other Study.62,63 Results of the DEKAN Study can be assigned as one of THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE the most important recent findings in the treatment of CAN. The 24. Spallone V, Maiello MR, Cicconetti E, Menzinger G. Autonomic neu- ropathy and cardiovascular risk factors in insulin-dependent and non- anti-oxidant alpha-lipoic acid should be considered as the most insulin-dependent diabetes. Diab Res Clin Pract 1997;34:169-79.
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