Significance of determination of hemodynamic phenotypes in early diagnosis of cardiovascular disorders in children with diabetes mellitus

Aim. To stratify hemodynamic phenotypes in children with diabetes mellitus and their frequency, depending on the duration of the disease.
Materials and methods. The study involved 72 children suffering from diabetes, aged 10 to 16 years who were divided into 3 groups. The first group – 22 children with diabetes mellitus up to 1 year. The second group – 24 patients with a disease duration of 1 to 5 years. The third group – 26 children with the disease over 5 years. Control group – 20 children, representative by age and sex.
All children underwent daily blood pressure monitoring (ABPM) with the ABPM-04 device (Meditech Ltd, Hungary). Diagnosis of latent hemodynamic disorders was performed by the method of quantitative analysis of the relationships of blood pressure parameters, which involved a linear regression of systolic blood pressure by pulse blood pressure. According to the results of regression, 6 hemodynamic phenotypes were determined, which characterized the individual features of the circulatory system: harmonic, myocardial-insufficient subtype of harmonic, borderline diastolic harmonic, borderline systolic harmonic, dysfunctional diastolic and dysfunctional systolic. According to ABPM results, the ambulatory arterial stiffness index (AASI) was calculated using a linear regression equation. The results were statistically processed using statistics software package Statistica 13.0 (StatSoft Inc., No. JPZ8041382130ARCN10-J).
Results. It was found that in the dynamics of diabetes the registration of the harmonic hemodynamic phenotype during the day decreased due to an increase in the proportion of patients with dysfunctional diastolic hemodynamic phenotype. At the same time, in children with diabetes, there was a significant increase in AASI from the first year of the disease with a progressive increase with its dynamics. The highest values of AASI were observed in dysfunctional hemodynamic phenotype.
Conclusions. In children with diabetes mellitus observed the formation of disharmonious hemodynamic phenotypes in the dynamics of the disease. In combination with increased vascular stiffness these changes realized in systemic circulatory disorders and the development of a diabetic angiopathy. Detected disorders, apparently, became the risk factors of hypertension. Determination of hemodynamic phenotype in children with diabetes mellitus can be used as screening method for preclinical diagnosis of latent disorders of the cardiovascular system, early treatment and prevention.

Diabetes is one of the growing challenges of the 21 st century. It has a negative impact on human health, and its growing prevalence has a significant negative economic effect. The number of patients living with diabetes in the world has tripled in the last 20 years. The rate of spread of the disease exceeds all forecasts: in 2010, it was projected that in 2025 the incidence will be 438 million, but according to the International Diabetes Federation, there are now 463 million people in the world with diabetes. More than 1.1 million of them are young people under the age of 20. The prevalence of diabetes among children in Ukraine is growing. Thus, in 2010 it was 0.981 per 1000 children, and in 2018 -already 1.2 [2].
One of the early and common complications of diabetes is damage to the cardiovascular system [10]. Diabetes appears as a separate and independent risk factor for fatal and nonfatal cardiovascular disorders [7]. In childhood, the formation of cardiovascular complications in insulin-dependent diabetes mellitus occurs simultaneously with the development of the disease [9]. Therefore, early diagnosis of cardiovascular messages at the stage before clinical changes is very important. At present, there are no clear objective signs of risk management of cardiovascular disorders in children with diabetes. Identification of latent messages of cardiovascular function in children with diabetes will allow to improve early diagnosis and optimize ways to correct established messages.

Aim
To stratify hemodynamic phenotypes in children with diabetes and the frequency with which they occur, depending on the duration of the disease.
children with a duration of diabetes up to 1 year (mean age 12.9 ± 0.4 years). The second group consisted of 24 patients with disease duration from 1 year to 5 years (mean age -13.8 ± 0.4 years). The third group included 26 children with diabetes for more than 5 years (mean age 14.3 ± 0.4 years). The control group consisted of 20 children representative by sex and age, who at the time of the survey had disorders of carbohydrate metabolism and intercurrent diseases. The groups were representative by age, sex, and body mass index.
All children under observation underwent a thorough clinical examination. Clinical examination of the patient included: medical history, clinical examination, laboratory and instrumental methods. Daily blood pressure monitoring with the ABPM-04 device (Meditech Ltd, Hungary) using the oscillometric method of blood pressure measurement was undertaken for all children. Patients under observation were diagnosed with latent hemodynamic disorders by quantitative analysis of blood pressure parameters [5], which involved a linear regression of systolic blood pressure by pulse blood pressure (by difference between systolic and diastolic pressure): where SBP -systolic blood pressure; DBP -diastolic blood pressure; PP -pulse pressure; Q is the regression coefficient, that characterizes the cross section (blood pressure in the area of the attenuating pulse wave at PP = 0). This indicator reflects the level of metabolism between blood and tissues; α is the angular regression coefficient ("pressor"), which reflects the proportional involvement of the heart and blood vessels in the process of blood flow; (α-1) -angular regression coefficient ("depressor"), reflects the inverse direction in relation to the "pressor" coefficient α participation in blood flow (elasticity of resistive vessels and skeletal muscle function).
According to the results of regression, 6 hemodynamic phenotypes were determined, which characterized individual features of the circulatory system functioning: harmonic, myocardial-insufficient subtype of harmonic, borderline diastolic harmonic, borderline systolic harmonic, dysfunctional diastolic and dysfunctional systolic ( Table 1) [5].
The ambulatory arterial stiffness index (AASI) was calculated according to the daily blood pressure monitoring (ABPM). AASI was calculated using a linear regression equation describing the relationship between systolic and diastolic blood pressure of the patient according to the results of ABPM and was determined by the tangent of the angle of the obtained regression line: where β 1 is the slope of the linear regression of DBP to SBP; β 2 is the regression coefficient.
The results were statistically processed using the statistical software package Statistica 13.0 (StatSoft Inc., No. JPZ8041382130ARCN10-J) with the determination of the arithmetic mean (M), standard deviation (σ) and mean errors (m). The median and quartile Me [Q1; Q2] were used for the uneven distribution of traits and the nonlinear dependence. The method of correlation analysis with calculation of Pearson's correlation coefficient is applied. Student's t-test and Fisher's angular transformation (criterion j) were used to assess the differences in the compared groups. In cases where the distribution law was statistically significantly different from normal, the nonparametric Mann-Whitney test (U) was calculated as a nonparametric analogue of the Student's test. Differences were considered significant at P < 0.05.
All procedures conducted in the children's studies complied with the ethical standards of the Institutional and National Research Committee and the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. Informed consent was obtained from all the individual participants included in the study and their guardians. Complete data established by children, their parents and the doctor, who confirm the results of this study, are not publicly available due to limitations obtained in the initial order.

Results
The analysis of parameters of hemodynamic phenotypes in children with diabetes mellitus showed that in the dynamics of diabetes mellitus there was an increased level of coefficients α and (α-1) during the day ( Table 2).
The detected changes became statistically significant in patients of group 3 (P < 0.05), in whom these coefficients were statistically significantly higher than both the control group and similar indicators of patients with disease duration up to 1 year (P < 0.05).
In the analysis of these coefficients, depending on the period of the day, attention was drawn to their increase at night in children with diabetes in the first year of the disease, which indicated an increase in the role of systolic component in blood circulation and reduced diastolic role. The most significant changes were registered in children of group 3, in which against the background of a 2.5-fold increase in the "pressor" coefficient, the value of the coefficient (α-1) became positive, indicating an excessive decrease in the role of peripheral vascular component. At the same time, there was a two-way change in the Q factor in patients with diabetes at different times of the day: its increase at day-time during the first 5 years of diabetes and a gradual decrease of this indicator at night. To date, it is known that low values of the coefficient Q are associated with the risk of developing acute hypotensive states [5]. Subsequently, we analyzed the frequency of variants of hemodynamic phenotypes in children with diabetes, taking into account the duration of the disease ( Table 3).
It was found that in the control group harmonic or myocardial-insufficient subtype of the harmonic phenotype dominated, which indicated the provision of blood circulation mainly due to the propulsive work of the left ventricle than the peripheral (vascular) component [5].
In the group of patients with diabetes mellitus lasting up to 1 year during the day, all children had harmonious hemodynamic phenotypes. At night, harmonious hemodynamic phenotypes were determined in the vast majority (72.7 %), borderline diastolic phenotype was observed in 9.1 % of patients, and a dysfunctional-diastolic hemodynamic phenotype was established in other 18.2 % of this group patients. However, the presence of dysfunctional and borderline circulatory phenotypes at night did not affect the overall hemodynamic phenotypes during the day in patients of this group, the analysis of which revealed the absence of pathological variants of hemodynamics.
We observed similar picture of the distribution of variants of hemodynamic phenotypes in the group of diabetic patients with disease duration from 1 to 5 years, among which harmonious hemodynamic phenotypes also dominated during the observation period.
In the long-term course of diabetes mellitus, the proportion of children with a harmonious hemodynamic phenotype during the 24-hour ABPM was statistically lower than among patients in the first 5 years of the disease (P < 0.05). It was noteworthy that the largest changes in hemodynamics in patients of this group were observed at night. Thus, if during the day harmonic hemodynamic phenotypes were determined in 62.5 % of patients, then at night we encountered these phenotypes 1.7 times less often -37.4 % of cases (P < 0.05). At the same time, the share of dysfunctional phenotypes at night increased by 2 times due to an increase in the number of patients with dysfunctional-diastolic hemodynamic phenotype (P < 0.05). Thus, if in the first 5 years of diabetes mellitus harmonious cardiovascular interaction in circulatory system was observed in patients mostly, then with disease duration over 5 years hemodynamic parameters in most patients corresponded to dysfunctional conditions, among which the diastolic-dysfunctional phenotype dominated.
Given the above, we analyzed the ambulatory arterial vascular stiffness index (AASI) ( Table 4). The analysis showed that in the majority (95.0 %) of children in the control group, the AASI values during the day were less than 0.3 arb. units, i.e. did not exceed the threshold between normal and high blood pressure in children [11].
At the same time, in children with diabetes, there was a significant increase in this index in all observation  The most significant increase of AASI was observed in patients with diabetes mellitus lasting more than 5 years compared with both the control group and the 1 st group of patients (P < 0.05). That is, the results showed a gradual increase in vascular rigidity with increasing duration of diabetes.
Individual analysis of AASI values confirmed our assumption. It was found that in the dynamics of the disease there was a decrease in the proportion of patients in whom the AASI index did not exceed the limit values (Fig. 1). If in the first year of the disease 45.4 % of children had normal AASI during the day, then with the duration of diabetes from 1 to 5 years, the number of children with normal values of this index decreased by 2 times and amounted to 23.1 % (P < 0.05). In Group 3 we saw the lowest number of patients with normal vascular stiffness index (12.5 %), which was 3.6 times less than in the first year of the disease (P < 0.05).
When analyzing the AASI index in patients with diabetes, depending on the time of day, similar changes were found. Thus, in the first year of diabetes, normal AASI values during the day were registered in 36.4 %. Subsequently, there was a decrease in the number of patients in whom this index did not exceed 0.3 arb. units up to 15.4 % in group 2 patients and 6.25 % in group 3 (P < 0.05).
The most significant changes in the AASI index were observed at night. If in the 1 st group 72.8 % of patients had normal AASI, then in patients of groups 2 and 3, respectively, only in 23.1 % and 18.7 % of children there was no increase in this index (P < 0.05). It should be noted that during the night period in the first year of the disease in no case was an increase in the AASI index over 0.5 arb. units. Also noteworthy was the fact that, in contrast to group 1, in groups 2 and 3 were found patients with pathological AASI values (more than 0.7 arb. units) both during the day (38.5 % and 37.5 %, respectively) and at night (7.7 % and 7.1 %, respectively), which may indicate severe vascular rigidity and the development of diabetic angiopathy. A direct correlation was established between AASI and PP values (r = +0.42, P < 0.05). These data are consistent with the results of other studies in which PP is considered as a sign of increased stiffness of the walls of blood vessels and, in particular, the aorta, and is a risk factor for cardiovascular disorders [1,8,11].
In order to clarify the relationship between hemodynamic features and the state of blood vessels, we further analyzed the parameters of hemodynamic phenotypes depending on the AASI ( Table 5). The analysis of the obtained data showed that in patients in whom the AASI exceeded the normative values, there was an increase in the coefficient α and a decrease in the coefficient Q, which indicated the development of hemodynamic disorders due to increased vascular stiffness. It was noteworthy that the statistical significance of these changes was acquired at night, which may indicate the development of nocturnal hypertension.

Discussion
The study revealed the features of hemodynamic phenotyping by blood pressure parameters in children with diabetes. It was found that in children with diabetes mellitus, in the dynamics of disease there was a deviation from the normative parameters of hemodynamic phenotypes: an increase during the day the level of "pressor" coefficient α, "depressant" coefficient (α-1) and bidirectional changes in Q (increase during the day and its decrease at night). The established changes indicate excessive involvement of the myocardium in the movement of blood due to increased cardiac output against the background of a significant weakening of the role of the "peripheral, vascular" component of the circulatory process [4]. At the same time, it is known that the coefficient Q reflects the blood pressure in the terminal part of the arterioles, where blood flow becomes constant (nonpulsating) and characterizes the level of metabolism between blood and organs [4]. In view of the above, it can be assumed that a moderate increase in Q is a positive adaptive phenomenon aimed at improving blood supply, in particular, to skeletal muscles, which is known to play an important role in glucose metabolism. Accordingly, a decrease in the coefficient Q at night by 1.5 times in patients of group 3 compared with the control group (P < 0.05), may be a risk factor for acute hypotensive conditions at night [5].
Further analysis of hemodynamic phenotypes revealed that children with long-term diabetes develop hemodynamic disorders, among the phenotypes of which diastolic-dysfunctional is dominating. It is believed that in this hemodynamic phenotype there are latent hemodynamic disorders, which are associated with increased vascular stiffness [3,5].
Confirmation of this assumption was a gradual increase in the outpatient arterial vascular stiffness index in the dynamics of diabetes. The diastolicdysfunctional phenotype of hemodynamics, along with high values of AASI, in the conditions of their long-term preservation, act as a risk factor for the development of hypertension in the future [5,6]. The formation of systolic dysfunctional hemodynamic phenotype in some children with diabetes mellitus may be a sign of increased total peripheral vascular resistance and is associated with the development of vascular spasms [5]. Therefore, patients with dysfunctional hemodynamic phenotypes, even in the presence of normotension, are at increased risk of developing hypertension and require dynamic monitoring.

Conclusions
1. In children with diabetes mellitus the dynamics of the disease demonstrates the formation of disharmonious hemodynamic phenotypes against the background of increased vascular stiffness, which in combination with increase in rigidity of vessels is realized by disturbance of systemic blood circulation and development and progression of diabetic angiopathy and, obviously, acts as risk factors of development of arterial hypertension.
2. Determination of hemodynamic phenotype in children with diabetes mellitus can be used as screening method for preclinical diagnosis of latent disorders of the cardiovascular system, early treatment and prevention.
Prospects for further research. In the future, it is planned to conduct a population study of hemodynamic phenotypes in children with diabetes mellitus.