Enhanced external counterpulsation (EECP) is a non-invasive and safe method for the treatment of stable coronary artery disease (CAD), including in the presence of changes in the coronary bed that do not allow for revascularization. [1]. In recent years, we have a tendency to expand the range of indications for the application of this method. The positive impact of EECP on quality of life, exercise tolerance, frequency of angina attacks, the need for nitroglycerin prepa­rations and the number of hospitalizations, as well as on the structural and functional state of the car­diovascular system, is being actively studied [2-6].

The study of EECP in the treatment of patients with CAD and type 2 diabetes mellitus (DM) deserves special attention. DM is a risk factor for the develop­ment and progression of CAD, and also significantly worsens the prognosis of patients after surgery [7-11]. According to the ISCHEMIA studies, patients with chronic CAD and DM had a worse prognosis for myocardial infarction (MI) and cardiovascular death compared with patients without DM [12]. The use of non-invasive adjunctive therapies could greatly facilitate the treatment of patients with CAD in com­bination with DM, as well as improve their quality of life. According to available data, the use of EECP helps to reduce the frequency of angina attacks in patients with CAD and DM and improve glycemic control [13][14]. Research by J.S. Martin et al. also showed a positive effect of EECP on peripheral vascular resistance and the functional state of the microvasculature in patients with impaired glucose tolerance [15].

We decided to investigate the results of this method in more detail, taking into account the ef­fectiveness of EECP in this group of patients, including assessing its potential effect on markers of glycemic control. In Russia, a study of the use of EECP in the treatment of patients with CAD and DM has not been conducted, despite the wide possibilities of using this method. The question of the effectiveness of such treatment remains open and requires further consideration.

The aim of this pilot study is to study the effect of EECP therapy on the functional status of patients, exercise tolerance, quality of life, structural and func­tional state of the vascular bed, as well as markers of glycemic control in patients with CAD and concomitant DM.

A prospective randomized study was performed at the University Clinical Hospital No. 1 (Sechenov University).

Inclusion criteria: age from 30 to 80 years, signed informed voluntary consent to participate in the study, verified CAD, as well as a confirmed diagnosis of DM. Exclusion criteria: history of thrombophlebitis and/or phlebitis; aneurysm of the thoracic or ab­dominal aorta; severe pathology of the valvular ap­paratus of the heart; high pulmonary hypertension (grade 2-3); arrhythmias affecting the synchronization of EECP with ECG; decompensated heart failure; un­controlled arterial hypertension (>180/110 mm Hg); coagulopathy; severe chronic lung disease; car­diac catheterization performed within 2-4 weeks before the study; treatment with anticoagulants with prothrombin time> 15 sec/INR> 3; pregnancy, breastfeeding; the presence of acute infectious dis­eases, or the patient's refusal to further participate in the study.

We examined 62 patients with stable CAD [class I-IV according to the classification of the Canadian Cardiovascular Society (CCS)] and DM (non-insulin-dependent), of which 30 patients were included in the study, meeting the inclusion/exclusion criteria. CAD was verified on the basis of coronary angiography (CAG) without coronary artery (CA) stenting (n=12), CAG with CA stenting (n=15), or CA bypass (n=3). 7 patients underwent myocardial infarction. All patients included in the study received optimal medical therapy (OMT) and were on an outpatient basis throughout the observation period. Hypoglycemic therapy in patients of both groups included biguanides, sulfonylurea derivatives, sodium-glucose cotransporter type 2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The study protocol was approved by the local ethics committee of the Sechenov University.

Patients were randomized using a random number generator (Statistica 12; StatSoft Inc.) into two groups of 15 people. During the first 7 weeks of follow-up, patients of the first group underwent a course of EECP in addition to OMT (35 hourly procedures, 5 procedures per week) using the EECP® Therapy Sys­tem Model TS3 cardiotherapeutic complex (Va­somedical Inc., USA). During the procedure, the pressure in the cuffs was in the range of 220-280 mm Hg. Control over the safety of treatment was carried out by monitoring adverse reactions during EECP procedures. Patients of the second group received only OMT without the addition of EECP.

All patients (n=30) at baseline and after 3 months were measured fasting glycemia (FPG) and post­prandial glycemia (PPG) to determine the dynamics of markers of glycemic control, as well as measured the level of glycated hemoglobin (HbA1c) and insulin resistance index (HOMA-IR). All patients underwent photoplethysmography (Angioscan-01, Angioscan, Russia) at baseline and after 3 months to assess the state of the vascular bed, as well as applanation tonometry (A-pulse CASPro, HealthSTATS, USA). Quality of life was determined using the SF-36 ques­tionnaire. A 6-minute walk test (6MWT) was per­formed to assess exercise tolerance. The study design is shown in Figure 1.

Statistical data processing was carried out using the Statistica 12 program (StatSoft Inc, USA). Analysis of the type of distribution of quantitative and qualitative ordinal variables was not carried out taking into ac­count the small sample size, so non-parametric sta­tistical methods were used. Results are presented as median and interquartile range (25%; 75%). Groups were compared with each other using the Mann-Whitney's U-test for quantitative and qualitative ordinal variables and two-tailed Fisher's exact test for categorical variables. The Wilcoxon's test for quan­titative and qualitative ordinal variables and McNemar's chi-square for categorical variables were used to assess changes in indicators from baseline (within each group). Delta-% was also determined to assess changes in quantitative and qualitative ordinal variables compared to the baseline, which was calculated by the formula: Δ%=N1-N0/N0×100%, where N0 is the value of the indicator initially, N1 is the value of the indicator in dynamics. Differences were considered statistically significant at a bilateral level of p<0.05. The size of each group was 15 people when calculating the sample size (calculator https://www.sealeden­velope.com/; alpha=5%, 1-beta=90%, non-infe­riority limit=10%), taking into account the effect size (dynamics of angina pectoris FC in studies using EECP; 8% in the control group, 42% in the experi­mental group).

The studied groups were comparable in terms of the main clinical and demographic indicators (Table 1).

During the follow-up period, patients in the EECP group didn't report side effects. In both study groups, we didn't observe cases of myocardial infarction, acute cerebrovascular accident and deaths. We noted an improvement in the angina pectoris FC according to the CCS classification in 8 patients (Table 2) on the background of ongoing therapy (EECP+OMT and only OMT).

We noted a significant increase in walking distance according to the 6MWT data when assessing the dynamics of exercise tolerance and quality of life in patients in the EECP group, as well as an increase in the physical and mental health components (Table 3).

According to photoplethysmography and appla­nation tonometry, in the EECP group we observed the dynamics of such functional indicators of the state of large vessels as phase shift (PS) and central aortic systolic pressure (CASP) (p<0.05), as well as the radial augmentation index (rAI) (p<0.05) asso­ciated with the structural state of the aorta. We also noted an increase in the occlusion index (IO) (p<0.001) and the functional index of the microvas­culature (Table 4). We noted a tendency to improve the structural parameters of large vessels (stiffness index [SI], p=0.069) and microvasculature (reflection index [RI], p=0.054). The dynamics of the studied parameters in the comparison group was insignifi­cant.

Positive dynamics in the EECP+OMT group was established in relation to FPG, PPG and HOMA-IR (p<0.05) (Table 5). During treatment, we didn't observe a decrease in the level of glycated hemoglobin. In the comparison group, no statistically significant results were demonstrated, although we observed a moderate decrease in PPG levels (p>0.05).

According to the selection results, only 30 patients met all the necessary criteria and successfully com­pleted the full course of EECP (35 hours). In total, 525 hours of counterpulsation were performed in the main study group.

The presence of diuretics among the drugs taken is due to the presence of chronic heart failure with congestion in the systemic circulation in 60% of the studied patients. The low need for drugs of the ni­troglycerin group is probably due to the selection of OMT and a decrease in the frequency and intensity of angina pectoris, as well as its equivalents, against this background. Only three of the 30 patients included in the study were taking short-acting nitrates, so we couldn't assess the change in the need for drugs in this group during EECP therapy.

The positive effect of EECP on the clinical status of patients and quality of life has been repeatedly con­firmed in previous studies [1][2][16]. The results of our work suggest that the effectiveness of EECP in relation to the effect on quality of life is also applicable to the group of patients with coronary artery disease and type 2 diabetes mellitus. The most significant subjective assessment was an increase in exercise tolerance, which was accompanied by an improvement in angina pectoris class according to CCS within 1.5 months after completion of the course. We observed an increase in walking distance in both groups due to the influence of both EECP and OMT. The increase in distance along the 6MWT in the EECP group after 3 months averaged 51 m (35; 65) or 18.2%, which was significantly higher (p<0.001) than in the OMT group.

Many links in the physiology of changes induced by EECP still remain unexplored, despite ongoing studies. One of the main points of effect of EECP on the structure and functional ability of the endothelium may be the protection of vascular endothelial cells from apoptosis [17]. The second key link in this mechanism is the improvement of endothelial function by increasing the shear stress of the vascular wall, which entails a decrease in the proliferation and mi­gration of smooth muscle cells, suppression of the formation of the extracellular matrix, and, as a result, this inhibits the development of atherosclerosis [18-20].

In this pilot study, such functional parameters of the vascular bed as PS and IO demonstrated statistically significant changes after 3 months of treatment only in the EECP group. Positive dynamics was observed in the analysis of the structural parameter of large vessels (rAI), and the functional parameter (CASP) (p<0.05). At the same time, no significant dynamics was shown in relation to such structural indicators as RI (microvasculature) and SI (large vessels) (p>0.05). The short duration of the study, as well as the severity of vascular changes in patients with coronary artery disease and type 2 diabetes mellitus, could lead to the result obtained.

One of the mechanisms by which EECP effects glycemic control may be shear stress. According to L.K. Walsh et al., the endothelium of arterioles sub­jected to intraluminal shear stress for 1 h becomes more insulin sensitive and an increase in insulin-in­duced dilatation of arterioles is observed [21]. This effect explains the decrease in the HOMA-IR insulin resistance index against the background of the EECP course, which was demonstrated, among other things, in our study.

P.D. Sardina et al reported in their study that EECP therapy reduced the concentration of advanced gly­cation end products and their receptors in this group of patients up to 6 months after treatment [22]. When assessing glycemic control indicators 48 hours and 2 weeks after the course, the authors found a decrease in FPG (-14.6 and -12.0%) and PPG (-14.6 and -13.5%), respectively [23]. In our study, the positive dynamics of glycemic control in the EECP group was 10.5% for FPG and 7.3% for PPG. The duration of the effect matters: 5 weeks after the completion of the EECP course (3 months from in­clusion in the study), the FPG and PPG values remained below the initial level. In the OMT group, a moderate, statistically insignificant decrease in PPG levels (p>0.05) was demonstrated, which is most likely due to the effectiveness of hypoglycemic therapy.

The absence of statistically significant dynamics of HbA1c in our study may be due to both the lack of effect of EECP on the dynamics of the indicator, and be a consequence of the low power of the study. This work was carried out as a pilot, and we are cur­rently planning to conduct similar work on a larger number of patients in order to further refute one of the two above hypotheses.

The main limiting factors in interpreting the results of this study were the small sample size and the ab­sence of a control group that would receive sham counterpulsation to eliminate the placebo effect of EECP therapy. In addition, the measurement of vascular bed parameters and short-term markers of glycemic control, not only at the stage before and 3 months after inclusion in the study, but also imme­diately after the completion of the EECP course, can make it possible to more accurately assess the dy­namics of the studied parameters.

In this pilot study, we demonstrated the positive effect of EECP on the state of the vascular bed, insulin resistance and glycemic control, as well as quality of life in such a difficult to treat group of patients as patients with coronary artery disease and diabetes mellitus. Currently, we continue to explore the possibilities of EECP, but many of the mechanisms and effects of this therapy remain unexplored. Thus, there remains a need to explore the possibilities of EECP in a large group of patients with coronary artery disease and concomitant type 2 diabetes mel­litus.

Relationships and Activities. None.

Funding: The study was performed with the sup­port of the Sechenov University.