Cardiac autonomic neuropathy (NAC) is a common complication, although little recognized, of diabetes mellitus (DBT), which is associated with an increase in cardiovascular mortality, with chronic nephropathy and increased morbidity in patients with DBT.Despite the high prevalence of the NAC, it usually remains without a diagnosis for prolonged periods, due to the lack of symptoms to advanced stages and the absence of consolidated strategies for its early diagnosis.

DBT is currently a global epidemic problem.It is estimated that there are 415 million people with DBT in the world and 318 million with glucose intolerance and with increased DBT risk.Cardiovascular disease (ECV) is the main cause of morbidity andt in the DBT, although microvascular complications have a significant impact.

The objective of this review was to update knowledge about epidemiology, pathogenesis, diagnosis, complications and treatment of NAC in patients with DBT.The authors conducted an exhaustive bibliographic review in the Pubmed, Google Scholar and Medline databases, focused on English studies published between 2012 and 2017.

epidemiology and risk factors

Studies have shown a wide variation in the prevalence of the NAC, which varies between 17% and 66% in patients with type 1 DBT (DBT1) and between 31% and 73% in subjects with type 2 DBT (DBT2).Part of these variations can be attributed to different diagnostic criteria, different populations and various risk factors.The risk factors for the NAC are common to other diabetic vascular complications, and include glycemic control, the duration of the DBT and the risks of ECV.

The duration of the DBT is a serious risk factor for the appearance of NAC in patients with DBT1 and DBT2.The informed incidence is between 2% per year (DBT2) and 6% per year (DBT1).The highest prevalences are correlated with the longest duration of the DBT.It has been reported that the prevalence of NAC is greater in the DBT2 than in DBT1, but this difference reflects the oldest of patients with DBT2.

Hyperglycemia plays an important role in the pathogenesis of the microvascular complications of the DBT and has an unfavorable impact on the evolution of the NAC and its progression.On the contrary, monitoring studies with intensive glymia control have shown significant and persistent reduction in the incidence of NAC.

Cardiovascular risk factors, such as obesity, smoking, arterial hypertension and hyperlipidemia have been associated with the appearance of NAC.Microvascular complications share common mechanisms and several studies have shown that their presence (retinopathy, microalbuminuria) also predicts the NAC.

Sex is a controversial risk factor.The Accord study, which included more than 8000 patients with DBT2, found higher prevalence of NAC in women than in men.This finding has not been confirmed by other recent studies.

The impact of ethnicity on the prevalence of NAC is also an issue in controversy.Several studies have indicated that white European patients with DBT have a higher prevalence of peripheral neuropathy (NP) than patients in Southeast Asia.However, several investigations have not been able to demonstrate variations in the prevalence of NAC between these populations.The authors of the review state that although the NP and the NAC share common pathogenic mechanisms, there are other specific ones for the appearance of NAC.

pathogenesis

Hyperglycemia can activate different paths involved in the pathogenesis of peripheral autonomic neuropathy

The Pathogenesis of the NAC is complex and multifactorial and is still in debate.Many ofThe proposed mechanisms are based on models of neuronal injury of somatic neuropathies and not of autonomic neuropathies.Some recent studies have shown that multifactorial intervention to reduce risk factors can avoid the progression of autonomic neuropathy, but has limited effects on somatic neuropathy, indicating different pathogenic mechanisms.

Hyperglycemia can activate different pathways involved in the pathogenesis of the NAC.Most of these pathways are related to the metabolic and oxidative state of neurons, with the presence of mitochondrial dysfunction and the formation of reactive oxygen species.Oxidative stress induces DNA damage and activation of metabolic pathways (path of polyol, hexosamine, etc.) that lead to the accumulation of neurotoxic products.Recent studies indicate that hyperglycemia also alters neuronal regeneration.

It is believed that the NAC can occur as a result of an autoimmune disease of the neurovegetative nodes.The presence of antibodies against the acetylcholinergic nicotinic receptor of the neurovegetative nodes can lead to serious autonomous manifestations, such as orthostatic intolerance, syncope, constipation, gastroparesia, urinary retention, xerostomy, xerophthalmia, anhydrosis and cognitive alterations.

The role of autoimmunity in the Diabetic Nac, however, is controversial.Some studies have shown an association between the presence of autoantibodies and neuropathic manifestations in DBT1.The association with the DBT2 has not yet been clarified.

Several genes have also been associated with the appearance and progression of the NAC and diabetic polyneuropathy, including TCF7L2, Apoe, Ace, Miri146a and Mir27a.Other researchers maintain a greater influence of environmental factors over genetic factors.

Obstructive sleep apnea syndrome (SAOS) is common in patients with DBT and has been associated with the appearance of diabetic polyneuropathy.Obesity is a known risk factor for SAOS, but some studies have shown a high prevalence of SAOS in diabetic patients without obesity.Proper compliance with the treatment of SAOS (positive pressure on airway) seems to improve neuropathic symptoms.The pathophysiology of the disorder is discussed.

Inflammation has an important role in the pathogenesis of DBT microvascular and macrovascular complications.The NAC is associated with increased inflammatory markers, such as C-Reactive protein, interleuquina (IL) 6 and tumor necrosis factor (TNF) alpha.The interrelation between inflammation and the NAC is not clear and bidirectional mechanisms between neural circuits and the modulation of the inflammatory response are postulated.It is known that the increase in vagal activity reduces the immune response and suppresses inflammation.

clinical manifestations and complications

The NAC becomes symptomatic only in the advanced stages of the disease.The denervation of the peripheral nervous system and the regional nervous system takes place in an ascending way.The vagus nerve is usually the first that is affected in the NAC, so patients usually occur with sympathetic predominance symptoms.The abnormalities of the baroreceptors and the changes in the variability of the heart rate appear with the progress of the disease.

Rest tachycardia, with a fixed heart rate (90 to 130 LPM), without variations with the respiratory phases, is associated with severe NAC and with complete cardiac denervation.Resting heart rate can be used as a diagnostic indicator and prognosis in patients with DBT.Rest tachycardia is linked to greaterrisk of mortality and cardiovascular complications.

Tolerance reduced to exercise can be a manifestation of NAC in the diabetic patient.Parasympathetic denervation and sympathetic predominance decrease exercise tolerance by reducing the appropriate increase in cardiac minute and heart rate, which normally take place during physical activity.

Orthostatic hypotension, defined as a reduction in systolic blood pressure & GT;20 mm Hg or a reduction in diastolic blood pressure & GT;10 mm Hg When moving from the supine position to standing, it is considered as a late manifestation of NAC.It is believed that it is due to the vasomotor denervation sympathetic, which produces an abnormal reflex arc, with peripheral vasodilation in standstation.

Symptoms may include dizziness, fades, vahids, presiding and syncopes.Some drugs usually indicated to diabetic patients (diuretics, vasodilators, tricyclic antidepressants, insulin) can aggravate these symptoms.

The most serious forms of the NAC include cardiac arrhythmias (prolonged QT interval syndrome), sudden death, silent myocardial ischemia and myocardiopathy.Several studies have shown that the NAC is strongly associated with silent myocardial ischemia, regardless of traditional cardiovascular risk factors.

Other complications of the NAC include an increase in anesthetic risk (intraoperative hemodynamic instability), pedias ulcers, sudomotor dysfunction, peripheral arteriopathy, puddle neuroarthropathy, chronic renal disease and anemia.The NAC is an independent predictive factor of global mortality and cardiovascular mortality.The informed five -year mortality rate for patients with DBT1 and DBT2 after NAC diagnosis is between 16% and 50%.Sudden death is the most frequent cause of death.

Systematic diagnosis and detection

Cardiac autonomic reflex tests (PRAC) or EWING tests are a specific test group that represents the reference diagnostic method for the NAC.A recent expert consensus has defined the NAC as the presence of at least two abnormal practices;The presence of an abnormal Practice is considered probable diagnosis of NAC, while two abnormal practices and orthostatic hypotension configure an advanced NAC.

The proof of the variability of heart rate with standing is the PRAC with better diagnostic capacity (sensitivity: 96%, specificity: 65%, negative predictive value: 94%, Odds Ratio: 21.14).

Other studies for Diagnosis of NAC include the spectral analysis of the resting heart rate, which evaluates thebeat variability to heart rate beat (an indicator of subclinical NAC), the spinder (allows a quantitative evaluation of the sympathetic cardiac innervation),the sensitivity tests of the baroreceptors (pharmacological or postural) and the confocal microscopy of the cornea (detects lesions of the corneal nerve fibers).

The expert consensus recommends the application of the evidence mentioned as a systematic detection of the NAC for risk stratification.

treatment

The increase in physical activity improves symptoms of regional dysfunction in DBT

Experts consider that NAC's early diagnosis is vital for therapeutic success, since available data suggests that cardiovascular denervation can be reversible if it is treated shortly after its start.The objectives of the treatment are the control of the symptoms and the brake on the progression of the disease.

The standard treatment today includes non -pharmacological measures andPharmacological (modification of lifestyle, intensive control of blood glucose and treatment of risk factors, such as hyperlipidemia and high blood pressure).The authors of the review highlight that the NAC and diabetic polyneuritis are two entities with common pathogenic mechanisms, but that effective treatments for one are not necessarily for the other.

Among the modifications of lifestyle, it has been shown that the increase in physical activity improves the symptoms of regional dysfunction in the DBT.Intensive glycemia control can reduce NAC incidence by 50% at six years in DBT1, compared to conventional treatment.A concentration of glucosylated hemoglobin & GT;7.5% is an independent risk factor for NAC.

Some antioxidants (alfalipoic acid, vitamin E, allopurinol, nicotinamide, C peptide, reductase aldosa inhibitors, angiotensin converting enzyme inhibitors) have been used in patients with NAC, although without conclusive results.Cardioselective beta blockers (Metoprolol, Propranolol) control the predominance of the sympathetic system over the parasympathetic system.

Orthostatic hypotension is a problem of difficult treatment.Recommendations include increasing water intake, avoiding sudden postural changes, using tight stockings in the lower limbs, ingesting small and frequent meals and avoiding physical maneuvers that increase intrathoracic or intra -abdominal pressure.Some drugs are associated with orthostatic hypotension and should be avoided, such as tricyclic antidepressants, diuretics and antagonists of alpha adrenoreceptors.Specific drugs for the treatment of orthostatic hypotension include mydodrine, fludrocortisone, octreotide, erythropoietin and pyridostigmine.

Conclusions

The NAC is a frequent condition in DBT patients, although it is often not diagnosed in a timely manner.This review updates epidemiology, pathophysiology, clinical manifestations, diagnosis, complications and treatment of NAC in diabetic patients

Source: Fisher V, Tahrani A Diabetes Metab Synd Obes.2017;10: 419–434