- The development of cardiac autonomic neuropathy (CAN) in patients with arterial hypertension and DM 2 can change the clinical course of these diseases.
- CAN in course of AH and DM 2 is manifested with heart rate variability (HRV), orthostatic hypotension (OH), symptoms of presyncope and syncope.
- Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire, the sitting-to-upright test, as well as supine-to-upright test are recommended for the diagnosis of OH and CAN.
- The risk factors of OH in this class of patients include age, body-mass index, poor control of DM, postprandial hypoglycaemia, sleep apnoea syndrome, type of drugs used in treatment of AH.
- The use of ambulatory blood pressure monitoring (ABPM) in comparison of office pressure measurement is recommended as more predictive tool of cardiovascular events. In this population of patients, BP phenotyping is important for risk stratification, the choice of treatment tactics and the achievement of target BP values.
AH arterial hypertension
BP blood pressure
CAN cardiac autonomic neuropathy
DBP diastolic blood pressure
DM diabetes mellitus
HRV heart rate variability
OH orthostatic hypotension
SBP systolic blood pressure
Peculiarities of the course of arterial hypertension (AH) in type 2 diabetes mellitus (DM) have been analysed in a large number of studies and are presented in clinical guidelines. At the same time, in the development of clinical guidelines, insufficient attention is paid to the problems of outpatient blood pressure (BP) control, daily BP variability and orthostatic hypotension (OH) . In this group of patients, BP phenotyping is important, as this makes it possible to identify patients with a higher cardiovascular risk and a less favourable prognosis.
According to the guidelines for the diagnosis and treatment of hypertension, the target level of blood pressure in patients with diabetes is defined as a blood pressure <130/80 mm Hg . In the ACCORD-BP, ONTARGET, ADVANCE and INVEST studies, it was noted that the smallest number of cardiovascular events among patients with a combination of hypertension and type 2 diabetes was seen at blood pressure levels of 125–139 mm Hg; a decrease in systolic blood pressure (SBP) below 120 mm Hg did not lead to a fall in the frequency of cardiovascular events and even contributed to an increase in the number of coronary accidents .
A problem with the clinical course of hypertension in patients with type 2 diabetes is the presence of cardiac autonomic neuropathy (CAN), which can lead to significant variability in heart rate and 24-hour BP, and may even be associated with OH. Pathophysiologically, diabetes-associated CAN is the result of complex interactions between glycaemic control, disease duration and systolic and diastolic blood pressure (DBP) levels, and it is associated with ageing and neuronal death. According to the EURODIAB study, microvascular changes in patients with diabetes mellitus, including retinopathy and albuminuria, are also associated with the progression of CAN .
Clinical criteria of orthostatic hypotension
Autonomic dysfunction (or CAN) is estimated to be present in 20% of patients enrolled in randomised trials and increases up to 65% of patients as they age and the duration of diabetes increases.
The clinical manifestations of CAN depend on the progression of the disease. Heart rate variability (HRV) is the earliest manifestation of subclinical CAN . Orthostatic hypotension and sympathetic cardiac denervation are manifestations of severe CAN. Clinical criteria for this condition are a decrease in SBP >20 mmHg or DBP >10 mmHg after changing the position of the body from a supine position to a standing position. Patients may present with symptoms presyncope (fainting, dizziness) and, in severe cases, with syncope. In addition, this includes changes in vision, variability in BP (both frequent decreases in pressure and nocturnal hypertension due to a paradoxical increase in sympathetic tone) .
Postural vertigo is an important manifestation of OH and a likely mediator of clinical events such as syncope . The authors here indicate that dizziness that lasts 1 minute or more after a change in body position is a predictor of OH. At the same time, with a duration of dizziness of less than 30 seconds and a rapid restoration of BP, the likelihood of OH is minimal. Studies also emphasise the importance of SBP rather than DBP in the development of vertigo symptoms .
The ACCORD study presents clinical criteria for orthostatic hypotension and indicates that the earliest signs of OH are more associated with dizziness on standing, while mean BP measurements at 3-minute intervals are associated with higher rates of OH. Also, the presence of this clinical symptomatology is mandatory in the dynamics of the course of the disease . According to the same study, high BP levels in the supine position may be correlated with a decrease in BP in the standing position. Orthostatic hypotension in DM patients is a manifestation of not only polyneuropathy, but also angiopathy. In particular, an inelastic artery can cause a defect in the baroreceptor reflex in the carotid arteries and aorta in order to maintain BP during orthostatic collapse .
According to diagnostic testing, CAN can be divided into 3 stages: 1) early, with proven variability of heart rate and BP in one study; 2) middle, damage to the heart and blood vessels with two or more abnormal results when monitoring heart rate and BP; and 3) late, severe damage in the presence of OH. The classification of the subclinical stage is based on changes in HRV or baroreflex sensitivity, without significant changes in HRV. The clinical stage is diagnosed when sympathetic activity predominates and symptoms, such as decreased exercise tolerance and resting tachycardia, appear .
It has been suggested that, due to the lack of specificity of autonomic symptoms, they do not represent a useful practical tool for diagnosing CAN. However, this idea has been called into question by recent results from the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire, designed around a complex profile of autonomic symptoms . It has been validated against CAN diagnostics and has proven satisfactory diagnostic accuracy [9, 10].
The Toronto Consensus recommends screening for orthostatic symptoms in any patient with diabetes, annual testing for hypertension, especially in patients over 50 years of age and those with hypertension who have unexplained tachycardia and QT interval prolongation .
Moreover, the sitting-to-upright test, instead of the standard supine-to-upright test, has recently been proposed as a simpler alternative when the standard method is less feasible, with a recommended threshold of 15 mm Hg for SBP and 7 mm Hg lowering of DBP .
Risk factors for orthostatic hypotension
Independent correlates of vegetative parameters in DM, according to the literature, are age, body mass index (BMI), waist circumference, other components of the metabolic syndrome, arterial hypertension and use of antihypertensive drugs, fasting glucose level and level of glucose 2 hours after exercise. The role of postprandial hyperglycaemia as a pathogenetic factor or risk marker for autonomic dysfunction and OH is also considered . In addition, sympathetic overactivity has been documented in insulin-resistant states. . Obstructive sleep apnoea syndrome (OSAS) also causes chemoreflex activation, further contributing to sympathetic hyperactivity .
It is assumed that orthostatic hypotension in diabetic patients is often associated with poor glycaemic control. Several studies have examined the relationship between HbA1c levels and the incidence of OH in patients with diabetes mellitus. A study by Wu et al, in Taiwan,  showed that diabetic patients with uncontrolled HBA1c levels had a 1.27-fold increased risk of OH. Hypoglycaemic conditions also lead to further progression of autonomic dysfunction and even greater changes in HRV, such as RMSSD, pNN50% and increased LF/HF.
The combination of ageing and DM increases the risk of OH. Several studies have reported that the prevalence of orthostatic hypotension in older adults with DM is approximately 28–30.5%.
Also, some drugs given to patients to control diabetes and hypertension, including diuretics, vasodilators, tricyclic antidepressants, and insulin, can exacerbate these symptoms [12, 13].
Effect of orthostatic hypotension on overall cardiovascular risk
One meta-analysis of 13 observational studies, including 121,913 patients with diabetes and hypertension with a mean follow-up of 6 years, found that the prevalence of orthostatic hypotension was associated with an increased risk of all-cause death, coronary artery disease, heart failure and stroke with a pooled relative risk of all-cause death of 1.78 for patients younger than 65 years and 1.26 for the older subgroup . In patients with diabetes and signs of OH, the risk of mortality associated with parasympathetic neuropathy is increased by 30-100% .
Among 4266 participants in the ACCORD study (aged 40 to 79 years) with verified OH at long-term follow-up (12 and 48 months), it was found that OH in 20% of patients was an independent predictor of all-cause mortality (hazard ratio 1.62) or hospitalisation due to progression of heart failure (hazard ratio 1.85) . Postural fluctuations in BP, hypertension in the supine position, and other consequences of impaired autonomic cardiovascular control are considered as possible mechanisms for excess mortality associated with OH .
Treatment of patients with diabetes mellitus type 2 with verified orthostatic hypotension
Orthostatic hypotension associated with severe CAN is treated symptomatically . Non-pharamacological treatments include exercise (such as squatting), slow posture changes or lifestyle changes (such as avoiding heavy carbohydrate-rich foods or increasing fluid intake) .
In some cases, pharmacological interventions are needed. Midodrine, an alpha-1-adrenergic agonist, is the only drug approved by the US Food and Drug Administration for the treatment of symptomatic hypotension [5, 16]. The main side effects of midodrine are paraesthesia, hypertension in the supine position, bradycardia, urinary retention and piloerection. Fludrocortisone is a mineralocorticoid drug that retains sodium and water, increases plasma volume and increases adrenergic sensitivity of blood vessels with side effects of hypertension in the supine position, hypokalaemia, heart failure and fluid retention . Erythropoietin, desmopressin, somatostatin analogues and non-selective beta blockers may also be used for symptomatic hypotension . Methods for the treatment of orthostatic hypotension in AH associated with type 2 diabetes are limited; however, early detection and lifestyle modification are important to limit the adverse effects of DM-associated severe CAN .
Early diagnosis of type 2 diabetes, based on screening data, good glycaemic control and risk factors, may mitigate the progression of CAN .
The role of ambulatory blood pressure monitoring
Four meta-analyses of the general population of hypertensive patients support the predictive role of daytime and nocturnal BP fluctuations on all-cause mortality, as well as cardiovascular mortality and events. Daily fluctuations in BP occur in type 2 diabetes patients even before the formation of diabetic nephropathy (DN), which is associated with autonomic dysregulation as a result of the development of diabetic autonomic cardiac neuropathy . Thus, atypical daily fluctuations in BP and orthostatic hypotension in AH patients with type 2 diabetes have common mechanisms.
The daily profile of BP in patients with diabetes has its own characteristics, differing from that in patients with hypertension without metabolic disorders. Against the background of metabolic disorders, a higher average level of both systolic and diastolic BP per day, in the daytime and at night, is revealed. In a significantly larger number of patients, there is an insufficient decrease in BP at night and nocturnal hypertension .
In addition, a feature of the daily BP profile in patients with DM is an increase in the variability of systolic and diastolic BP during the daytime and at night. BP variability correlates with more severe target organ damage and is considered as a factor of poor prognosis in patients with AH. Patients with type 2 diabetes and hypertension are also characterised by a wide range and speed of the morning rise in blood pressure. For patients with type 2 DM in combination with AH, a perversion of the normal circadian rhythm of arterial pressure turned out to be typical. It was revealed that there was no adequate night-time decrease in both SBP and DBP, which is associated with damage to the autonomic nervous system.
Among patients with type 2 diabetes with hypertension, only 28.1% of patients have a normal circadian BP biorhythm (dipper patients), and for 71.9% of patients with DM suffering from AH, a perversion of the circadian rhythm of arterial pressure is characteristic. Thus, the diagnosis of latent hypertension in type 2 diabetes in most cases is based on the level of nocturnal BP, which emphasises the importance of 24-hour ambulatory blood pressure monitoring (ABPM) in this population [1, 2].
At the same time, analyses of international databases show that, as a rule, DBP decreases to a greater extent than SBP . The importance of an insufficient nocturnal reduction in SBP and nocturnal hypertension for the development of target organ damage and the prognosis of cardiovascular complications has also been shown . The ELSA study  showed the role of 24-hour mean pulse BP as a risk factor for end-organ damage and cardiovascular morbidity and mortality.
To date, a relatively small number of studies have been published on the study of BP phenotypes in patients with DM . Meta-analyses of prospective studies in the population of people with normal blood pressure and patients with hypertension show that the results obtained with ABPM are a better predictor of cardiovascular events compared with conventional office blood pressure measurement [1, 20].
Thus, phenotyping of patients with DM according to variants of clinical and/or ambulatory BP disorders may be of great importance in risk stratification and choice of treatment tactics. At the same time, the frequency of 24-hour ABPM in this population in real clinical practice is relatively low. Despite the recommendations of the European Society of Cardiology/European Society of Hypertension for the management of hypertension , indicating the need to measure BP in the supine and upright position in people with diabetes, there remains a need for awareness, detection and treatment of this condition in clinical practice.
In addition, the extent of CAN detection indicates the relevance of this problem. Data on autonomic dysfunction in diabetes is increasing. Thus, CAN is a new surrogate point and may become a new target for prevention. There is supporting evidence for the prognostic value of CAN and growing evidence for its central role in cardiovascular disease.