A New Algorithm for the Selection and Risk Stratification of Patients for the Efficient Aerobic Cardiorespiratory Training after Coronary Artery Bypass Surgery

Abstract

The introduction of the strategically new algorithm for the preparing cardiac patients for aerobic exercise trainings of different intensity, with the transition from constant moderate-intensity training to high-intensity interval training, fundamentally changes medical approaches to cardiac rehabilitation after open heart surgery. We have developed such algorithms with the best combination of cardiovascular and non-cardiovascular parameters in patients after CABG.

1. Introduction

In the recent past, patients who survived myocardial infarction were recommended bed rest for several weeks [1]. That was the common tactic. Currently, patients both after coronary artery stenting and after coronary artery bypass grafting are recommended aerobic physical trainings in complex postoperative treatment to improve functional capacity and reduce the risk of hospitalization and mortality [2].

It is of key importance to understand what the physiological mechanisms are that aerobic physical training influences the function of the cardiovascular system in patients with ischemic heart disease.

Randomized as well as non-randomized clinical trials, observational and case-control studies have proven that physical trainings significantly modify cardiovascular mortality risk and reduce major cardiovascular and cerebrovascular events [3, 4]. According to these studies overall mortality reduction has been beneficial in post-acute coronary syndrome and post-coronary artery bypass surgery (post-CABG) patients. The specific mechanisms by which physical activity reduces mortality and cardiovascular complications are likely to be multifactorial and go beyond reducing cardiovascular disease (CVD) risk factors, as positive effects have also been observed on thrombosis, cardiac performance, cardiac remodeling, endothelial function, inflammation, and autonomic nervous system activity (Figure 1). It has been found that favorable impacts of exercise training on thrombotic modification are mediated by suppressed pro-thrombogenic factors and enhanced anti-thrombogenic factors [5]. Physical activity decreases exercise induced plasma catecholamine levels and down-regulates platelet α₂-adrenergic receptor performance, thereby reducing Von Willebrand factor-platelet interaction. Moreover, exercise training enhances substantial nitric oxide (NO) release from platelets and endothelium. Exercise training provides protection against oxidative stress by increasing NO bioavailability determining anti-hypertensive effects [6]. While managing oxidative stress exercise training facilitates reduction of systemic inflammatory markers. The increased content of mitochondria in muscles during exercise training promotes fat oxidation preferentially rather than carbohydrate oxidation. This adaptation reduces lactate production and provides longer training durations while increasing aerobic capacity. Improved cardiac performance mechanism lies through angiogenesis in muscle, mediated by B-adrenergic stimulation of capillary growth by vascular endothelial growth factors and platelet-derived growth factors. These processes are stimulated by insulin-like growth factor-1, proportionally expressed during exercise, and have been shown to reverse cardiac remodeling in animal models. Study by Soci UPR and co-authors [7] showed that post-transcriptional gene regulation associated with exercise training by microRNAs reduces remodeling through interactions between metabolic, contractile and epigenetic genes. Angiotensinogen II modulation during exercise training causes alterations in systemic vasoconstriction, sodium and water retention, and aldosterone production. Decreasing aldosterone lowers sympathetic tone. Another mechanism of regulating sympathetic tone is through the actions of plasma adrenomodullin [8] and atrio/brain-natriuretic-peptides which are tied closely to aerobic consumption [9]. These molecules attenuate blood pressure by suppressing noradrenaline and endothelin-1, improving endothelial responsiveness and function. Regular physical activity increases parasympathetic tone in sympathovagal signaling resulting in heart rate variability changes towards better prognosis.

Figure 1.

Physiological and psychological effects of aerobic physical trainings in ischemic heart disease patients.

A key requirement for the function of the cardiovascular system during exercise is to ensure the delivery of the necessary amount of oxygen and other nutrients to the working muscles. To this end, muscle blood flow during physical work increases tremendously [10]. The relationship between cardiac output and peripheral muscle function, and between oxygen consumption and peripheral muscle performance at different load levels, is linear. Muscle work increases the need for oxygen, and this, in turn, leads to the expansion of muscle blood circulation, increasing venous return and cardiac output [11]. In physical training, the proportional contribution of the change in heart rate to the increase in cardiac output is undoubtedly higher than the proportional contribution of stroke volume. The stroke volume normally reaches its maximum by the time the cardiac output increases only to half of its maximum. Any additional increase in cardiac output is possible only through an increase in the heart rate. The power of the load performed by patients depends not only on central hemodynamics, but also on the processes that develop in the myocardium of the right and left ventricles in chronic heart failure.

The interest of most researchers, including our interest, is focused on assessing the impact of physical training on the functional ability of the cardiovascular system and the physical performance of cardiac surgery patients who have undergone heart surgery.

To assess the condition of patients who have undergone coronary artery bypass grafting (CABG) surgery and the choice of the optimal training program, the analysis of the risk of adverse events associated with physical training, as well as cardiorespiratory readiness, is of ongoing interest. The introduction of strategically new algorithms for preparing cardiac surgery patients for physical training programs of varying intensity, with the transition from constant moderate-intensity training to high-intensity interval training, makes it possible to fundamentally change medical approaches to cardiac rehabilitation after open-heart surgery.

Till now are published 7 international protocols for cardiac risk stratification to conduct effective and safe training programs in adult patients with cardiac pathology, mainly with coronary heart disease. These are the protocols of the American Association for Cardiovascular and Pulmonary Rehabilitation [12], the protocol of the American College of Sports Medicine [13], the American Heart Association [14], the protocol of Frederick Pashkov [15], the protocols of the Brazilian Society Cardiology [16], the French Society of Cardiology [17] and the Spanish Society of Cardiology [18]. An analysis of these protocols showed the lack of uniform standards and discrepancy in this matter [19] (Table 1). Differences were valued in the statistical significance range of 5% and in most protocols additional studies were conducted to identify cardiac risk of cardiovascular events. The most used test for these purposes was the ergospirometry test. This method has high specificity and reliability, allows to detect myocardial ischemia, arrhythmias, and most importantly, gives the value of the MET (metabolic equivalent) indicator.

Risk stratification (RR) protocols for CVD patients participating in cardiac rehabilitation (CR)				Reference
	Category of patients included	Parameters used for RR	Risk groups
American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR)	Patients after MI, coronary revascularization	Stress-test with METs, ischemia, angina symptoms, silent ischemia, arrythmias, LV EF, BP, HR, CHF symptoms	Low, medium, high	[12]
American College of Sports Medicine (ACSM)	Patients with CVD and any other individuals	Stress-test with METs, ischemia, angina symptoms, silent ischemia, arrythmias, LV EF, BP, HR, CHF symptoms	Low, medium, high	[13]
American Heart Association (AHA)	Patients with various CVD, including congenital and acquired heart diseases, post-CABG, after stenting, chronic heart failure (CHF)	Stress-test with METs, ischemia, angina symptoms, arrythmias, LV EF, BP, CHF symptoms	Low, medium, high	[14]
F. Pashkow (USA)	Patients after MI, coronary revascularization	Stress-test with METs, perfusion and kinetical defects during stress tests, ischemia, angina symptoms, arrythmias, late ventricular potentials assessed by high resolution ECG, LV EF, BP, CHF symptoms	Low, medium, high	[15]
Brazilian Society of Cardiology (BSC)	Patients after MI, coronary revascularization	Stress-test with METs, ischemia, arrythmias, LV EF, BP, CHF symptoms	Low, medium, high	[16]
French Society of Cardiology (FSC)	Patients after MI, coronary revascularization	Stress-test with METs, ischemia, angina symptoms, arrythmias, LV EF, BP, CHF symptoms; echo- and ECG stress tests, anamnesis	Low, medium, high	[17]
Spanish Society of Cardiology (SSC)	Patients after MI, coronary revascularization	Stress-test with METs, stress-test with Thallium; ischemia, angina symptoms, arrythmias, LV EF, BP, CHF symptoms; VO2 max for competitions	Low, medium, high	[18]

Table 1.

Risk stratification (RR) protocols for CVD patients participating in cardiac rehabilitation (CR).

CVD—cardiovascular diseases; RR—risk stratification (risk of morbidity and mortality, associated with exercise trainings); MI—myocardial infarction, BP—blood pressure, HR- heart rate, CHF—chronic heart failure, LV EF—left ventricular ejection fraction, ECG—electrocardiogram, MET—Metabolic equivalent, used for the assessment of baseline physical activity and exercise tolerance during stress tests, measured through the determination of peak oxygen consumption—VO₂ at rest.

In the Russian clinical guidelines for cardiac rehabilitation and secondary prevention of patients after CABG, there is no risk stratification protocol for the selection of patients after CABG to conduct effective aerobic cardiorespiratory trainings (CRT), only a gradation by functional classes of chronic heart failure (CHF) is presented [20].

With all the above in mind, the aim of our study was to develop new approaches to the selection of patients after CABG for the efficient and safe aerobic CRT.

2. Materials and methods

2.1 Study design and study subjects

The study included 137 patients (70 men, 67 women, mean age 68.5 ± 8.3 years) after CABG at the A.N. Bakulev National Medical Research Center for Cardiovascular Surgery. 90.4% of patients after CABG were classified as being in first functional class chronic heart failure. Mean left ventricular ejection fraction was 58% ± 5.6. 47.8% of patients underwent on-pump CABG and 52.2% of patients underwent off-pump CABG. In most cases 3 vessel CABG was performed.

After surgery, all patients underwent a set of clinical, instrumental and laboratory research investigations, including standard electrocardiography, a test with physical activity on a treadmill/ergospirometry test, a 6-minute walk test, Holter ECG monitoring, transthoracic echocardiography, as well as standard laboratory examinations: complete blood count (hemoglobin, erythrocytes, hematocrit, platelets, leukocytes), biochemical blood test (total protein, albumin, creatinine, urea, alanine aminotransferase - ALT, aspartate aminotransferase - AST, glucose, potassium, sodium, total cholesterol, low and high density lipoproteins) and blood coagulation status (prothrombin time, international normalized ratio, activated partial thromboplastin time, degree of platelet aggregation).

Prior to surgery, all patients underwent coronary angiography, duplex scanning of the extracranial part of the brachiocephalic arteries and arteries of the lower extremities.

Patients who were unable to perform a 6-minute walk test, with a hemoglobin level of less than 95 g/l, with an ALT level of more than 40 U/l, hepatitis, liver dysfunction, liver cirrhosis, and with Gilbert’s disease were excluded from the study. Patients with neurological disorders were also excluded from the study. Orthopedic disorders and severe atherosclerosis of the arteries of the lower extremities, which limited the ability to participate in training programs were also among exclusion criteria. The clinical characteristics of patients are presented in Table 2.

Variables	Patients after CABG
Number of patients, n, absolute number	137
On pump CABG/ off pump CABG (%)	47.8%/52.2%
Male	51%
Female	49%
Mean age (years)	68.5 ± 8.3
Body mass index	26.8 ± 5
METs	6.3 ± 0.3
Mean left ventricular ejection fraction (%)	58 ± 5.6
Chronic heart failure class I (number of patients %)	100%

Table 2.

Clinical characteristics of patients assigned to cardiorespiratory trainings (CRT).

MET—Metabolic equivalent is the amount of exertion that corresponds to a state of rest. MET is measured through the determination of peak oxygen consumption—VO₂ at rest. It represents the baseline physical activity level.

Major endpoints of the study included: risk stratification of adverse events associated with exercise training after CABG, determination of groups of patients with low, medium, and high levels of physical readiness for aerobic physical CRT of different intensity based on the use of clinical, instrumental and laboratory indicators such as the FIT-treadmill index, ALT (alanine aminotransferase) and the level of postoperative hemoglobin. Study design is presented as Figure 2.

Figure 2.

Study design.

2.2 Exercise protocol

For exercise training in our study, we used ERG 911 bicycle ergometers manufactured by Schiller (Switzerland). Aerobic physical training on bicycle ergometers was carried out for 4 weeks: it started 30 days after the surgery and then continued on an outpatient basis. In the first 7 days, training was carried out with a Pulse-steady-state protocol, the second week - with a ramp interval protocol. First week the duration of the exercises was on average 20 minutes, in the second week – 30–35 minutes.

In a pulse-steady-state protocol, heart rate training and ergometer load are interrelated, with the ergometer load being an adjustable parameter. The load of the ergometer is adjusted to maintain a constant “training heart rate”. In addition to the training itself, this program is very suitable as a reference for comparing with other training programs. The exercise regimen was calculated using ergospirometry data based on the maximal or peak VO_2.

The ramp interval protocol is a protocol with a linear increase in load between two levels with heart rate control. The workload in this program includes two levels, which replace each other. The load at which the training heart rate is first reached serves as a reference load to determine the lower return point, calculated by subtracting a certain value from the upper load level. As soon as the training heart rate is reached the load will be continuously reduced to the lowest point of return.

Regarding the intensity of aerobic physical training, we used trainings of moderate and high intensity. In moderate intensity training the goal was to reach 60–75% of peak oxygen consumption (VO₂). In high-intensity training, the goal was to reach 80–85% of peak oxygen consumption (VO₂). The choice of training intensity method was based on the patients’ belonging to certain groups and a linear relationship between heart rate and VO₂. In our study we used high-intensity interval training (HIIT) programs with a 4-minute high-intensity workout regimen followed by intermediate 3-minute rest breaks (Nordic model) as well as constant training programs of moderate intensity (MICT). The intensity and mode of training were determined individually depending on the level of physical readiness of patients based on the developed algorithm. As a follow up, patients were advised to continue physical training individually based on the selected type of training. Remote monitoring of exercising patients within the study lasted from 4 months (120 days) to 1 year to assess survival, mortality, and morbidity.

2.3 Assessment of risks associated with physical training

One of the main endpoints of our study was to determine the predictive role of the RARE scale in the development of adverse events due to physical training on the example of our patients after CABG.

Patients were divided into groups depending on the low or high risk of adverse events according to the well-known and generally accepted scale of assessment of risks associated with physical training (RARE score) [21]. The RARE (risk of activity related event) scale considers resting heart rate, resting blood pressure, functional activity in METs, ischemic events according to the well-known classification of angina pectoris and ST segment changes, left ventricular ejection fraction, and the presence or absence of arrhythmias. Each of the indicators is assigned a value from 0 to 4, except for heart rate and blood pressure, which are assigned 2 points. The RARE scale is determined by summing the scores of all six of the above indicators and can range from 0 to 20 points. Patients with a score of ≥4 are at high risk of adverse events, and patients with a score of <4 are at low risk.

In the RARE scale, there are 5 large criteria, which are assigned 4 points: <6.0 METS exercise tolerance, LVEF <20% (left ventricular ejection fraction), recurrent VT (ventricular tachycardia)/VF(ventricular fibrillation) in the absence of AMI (acute myocardial infarction), or severe ischemia (III-IV FC according to the Canadian classification CCS, ST-segment depression more than 2 mm, multivessel lesion of the coronary arteries/proximal significant stenosis of anterior interventricular descendance or stenosis of the trunk of the left coronary artery. Thus, the RARE score identifies high-risk patients with a combination of small criteria, such as hypotension with moderate left ventricular dysfunction, atrial fibrillation (AFIB) with a frequent ventricular response, or angina pectoris II FC according to CCS with a moderate decrease in exercise tolerance.

The group of higher risk of developing adverse events during physical training on the RARE scale included patients of the older age group, female, with diabetes and hypertension, and a high body mass index (Table 3). Carotid atherosclerosis was prevalent in the higher risk group.

Variables	Low risk (n = 96)	High risk (n = 41)	p
Age, years	61 ± 11	67 ± 10	<0.001
Gender m/f, (number of patients %)	M-77%/F-23%	M- 48%/F- 52%	0.017
Waist, size in cm	85 ± 13	108 ± 16	<0.001
Weight, kg	86.8 ± 17.5	88.5 ± 21.4	0.3
Body mass index kg/m^2	29.6 ± 5.3	31.1 ± 6.9	0.03
Heart rate, beat/min	67 ± 13	67 ± 14	0.483
SAP, mmHg	118 ± 15	121 ± 19	0.02
DAP, mmHg	73 ± 9	71 ± 11	0.034
Left ventricular EF, (%)	61.5 ± 8.6	56.5 ± 13.5	<0.001
METs	8.4 ± 1.9	5.8 ± 1.5	<0.001
Total cholesterol, mmol/l	3.56 ± 1.01	3.7 ± 1.2	0.087
HDLP mmol/l	1.17 ± 0.31	1.15 ± 0.34	0.481
LDLP mmol/l	1.8 ± 0.82	1.88 ± 0.95	0.26
TG, mmol/l	1.3 ± 0.77	1.53 ± 1.39	0.007
HbA1c,%	6.1 ± 0.8	6.7 ± 1.2	<0.001
Arterial hypertension (%)	49	60	0.004
Diabetes type 2 (%)	21	36	<0.001
AT of carotid arteries, %	8	20	0.002

Table 3.

Characteristics of post CABG patients with low risk (< 4 points) or high risk (≥4 points) of developing adverse events associated with physical trainings based on RARE score.

2.4 Assessment of survival by FIT treadmill index

There are 3 components to physical training: frequency (how many times a week the training takes place), intensity (how intense the load is during training), and time (how long the training lasts). All these 3 points make up the FIT formula (F = frequency, I = intensity, T = time). By correctly combining all 3 points trainings can be planned most effectively.

With the advent of fitness, it became possible to establish a reliable survival rate in patients engaged in fitness, that is, aerobic cardiorespiratory and other types of training. As part of Henry Ford’s Physical Training Testing and Evaluation Project, the FIT treadmill score (FIT treadmill index) was calculated [22]. It allows clinicians to calculate and predict the 10-year risk of survival and mortality in healthy individuals and fitness patients.

FIT treadmill index =85% maximal predictive HR + 12 × (METs)-4 × (age) +43 if the patient is female.

Survival = 0.014 (%Max. predictive heart rate + 0.182 (METs) + 0.6381 (female) - 0.0613 (age).

FIT treadmill index was adjusted after CRT (cardiorespiratory training) programs: FIT treadmill index ≥100 meant very low mortality risk, FIT treadmill index 1–100 defined low risk, ≤0 to −100 - intermediate risk, ≤ − 100 to −200 high risk. FIT treadmill index ≥100 is associated with 2% risk of mortality in 10 years. FIT treadmill index between “-100” and “-200” is associated with 38% risk of mortality in 10 years.

The Treadmill FIT Index serves as a quantitative expression of cardiorespiratory fitness for participation in training programs. It’s easy to calculate. It does not depend on symptoms, and is not limited to electrocardiographic changes, but includes age factor and gender in the calculation of risk. Moreover, in addition to determining the risk during training programs and prognosis of coronary artery stenosis, it makes it possible to predict long-term survival. The METs indicator is decisive and universal in the selection of patients for cardiac rehabilitation, and the FIT index, in the calculation of which METs is used, can serve as an additional factor for determining cardiorespiratory fitness.

2.5 Blood measurements

All patients underwent a complete blood count with the determination of hemoglobin, erythrocytes, platelets, leukocytes; biochemical blood test, including AST, ALT, glucose, creatinine, alkaline phosphatase, lipid profile. ALT activity was assessed using the standard Beckman Coulter test. Quantification was carried out using kinetic UV tests. In order to ensure the maximum catalytic activity of the ALT level in the blood, activated peroxidase phosphate, which is a necessary co-factor for the catalytic activity of ALT, was added to all tubes.

In our center, the following reference values have been determined: ALT 10–40 U/L, AST 10–42 U/L.

The reference values of the lipid profile are as follows: total cholesterol 3.1–5.2 mmol/L, Triglycerides 0.4–1.81 mmol/L, HDL 0.75–2.31 mmol/L, LDL 0–3.9 mmol/L, creatinine 53–115 μmol/L.

2.6 Statistical analysis

Statistical data processing was carried out using SPSS 22.0 and SAS, version 9.3. The indicators are represented by mean and standard deviation (M ± SD) data. Qualitative indicators were presented in % of the total number of patients in the sample or in the corresponding group. To compare the performance of the two groups, the chi-square test, the Fisher (F) test for small samples, the Wilcoxon Matched Pairs Test, the Mann-Whitney U Test, and its modification of the Mann and Whitney U-test were used. In the case of more than two independent samples (in the analysis of indicators in 3 groups), the H-test according to the Kruskal method and Wallis (Kruskal - Wallis one-way analysis of variance) was used. In the case of a near-normal distribution, the Student’s test was also used to compare the two samples. Correlation analysis was performed using Spearman’s rank correlation. The differences were considered statistically significant at p < 0.05.

A univariate regression analysis was performed using Fisher’s x2 test and Student’s t-test. Statistically significant parameters (p < 0.05) were introduced into a multivariate regression analysis (generalized logistic model) to identify independent predictors; The selection of significant features was carried out using a standard step-by-step procedure with the inclusion of variables. Survival curves were assessed using the Kaplan-Meier method and a hazard ratio with a 95% confidence interval.

3. Results

3.1 The risk stratification of adverse events associated with physical trainings after CABG

A total of 11 adverse events were recorded in the study, including 8 events in the high-risk group and 3 events in the low-risk group. All these were small events – symptomatic hypotension, hypertension, symptomatic tachycardia, in one case a short episode of atrial fibrillation (AF), ventricular bigeminy and ST-depression up to 1 mm along the anterolateral wall of the LV. The development of adverse events in our study associated with aerobic CRT is low 0.8% (11 adverse events per 1370 hours of training).

Analysis of the dependence of the sensitivity of the scale on the frequency of false-positive results showed the diagnostic reliability of the threshold value of the RARE scale ≥4 points in assessing the risk of developing adverse events due to physical training. According to linear regression analysis high-risk group had a significant predictive significance in the development of low-risk events (R = 0.09, B = 0.023, P = 0,024) and there was a tendency to increase the risk of adverse events with the growth in the RARE scale (relative risk 4.2; Χ² = 5,12; p = 0.024, power 0.62) (Figure 3).

Figure 3.

The dependence of the sensitivity of the RARE scale on the frequency of false-positive conclusions (p = 0.024).

The low positive predictive value of the RARE score of 3.1% according to linear regression analysis in our study indicates that it is necessary to concentrate on identifying patients who have a low, rather than high, risk of developing adverse events during physical training. In this respect, the RARE scale accurately gives the possibility to determine patients with low risk, since none of the patients in this group had large/significant complications and the vast majority were free from any events in the long-term period.

3.2 The role of laboratory parameters in the selection of patients after CABG for aerobic CRT

When determining the role of laboratory parameters for the selection of groups after CABG with a low, medium, and high level of readiness for aerobic CRT, attention was focused on 2 indicators of hemoglobin and ALT levels. According to the recommendations of the European Society of Cardiothoracic Surgeons, the hemoglobin level ≤ 100 g/l after CABG is considered the threshold for entry into cardiac rehabilitation programs and it is proposed to refrain from starting aerobic CRT [23]. With hemoglobin of 100 g/l or less, the tolerance to physical activity, determined by the test with a 6-minute walk, is significantly lower.

In our study, a hemoglobin level of 100 g/L was detected in 55 (40.15%) out of 137 patients (including 10 women, 45 men) before the onset of CRT. In 82 patients (60%), the hemoglobin value was more than 100 g/l and ranged from 100 to 130 g/l. Before the onset of aerobic CRT in the subgroup of patients with hemoglobin 95–100 g/l, the average distance during the 6-minute walk test was 258 ± 106 meters, while in the subgroup of patients with hemoglobin more than 100 g/l 306 ± 101 meters (p = 0.007). The maximum METs on the treadmill, the maximum heart rate and the threshold heart rate were significantly lower in the hemoglobin group of 95–100 g/L. Depression of the ST segment of a non-ischemic nature, as well as the inversion of the T-wave and single VE during exercise also occurred significantly more often in patients with hemoglobin 95–100 g/l. At a hemoglobin level of 100 g/l or less, the distance covered in meters during a 6-minute walk test was significantly lower, and in these patients, there was a significant increase in that distance after the course of CRT.

Generally, in all patients, the average distance in meters for 6 minutes increased from 298 ± 100 meters (before the onset of CRT) to 431 ± 90 meters at the end of the CRT course (p = 0.001) (Table 4). Thus, even if exercise tolerance is reduced with a hemoglobin value of less than 100 g/l, the absolute value of the 6-minute walk test is acceptable (200 m). Moreover, this “gap” in exercise tolerance is fully restored in 7 weeks (49 days) of CRT, when physical fitness no longer depends on hemoglobin values.

Hemoglobin (g/l)	Distance in meters by 6 min walk test before CRT	р (between groups)	Distance in meters by 6 min walk test after CRT	р(between groups)
95–100	258 ± 106		415 ± 73
100–130	306 ± 101	0.007	437 ± 95	0.166

Table 4.

Distance covered by 6-minute walk test in patients with different hemoglobin level before and after cardiac respiratory trainings (CRT).

It has been proven and known that the alanine aminotransferase - ALT threshold level of ≤17 U/L is associated with an increased probability of long-term mortality in patients with coronary heart disease [24, 25]. Considering the significant prognostic role of ALT in large studies, we divided our patients into groups depending on the ALT serum level.

It turned out that in the group of patients with an ALT level of ≤17 U/L, exercise tolerance measured in METs and exercise duration was significantly lower, resting heart rate was significantly higher and reserve heart rate was significantly lower (Table 5).

	ALT≤17 U/l	ALT≤40 U/l
METs	6.86 ± 0.2	7.83 ± 1.5	p 0.01
Test duration (min, sec)	6 min 41 sec ± 1.5 min	8 min 44 sec ± 2.5 min	p 0.01
Rest heart rate, beat/min	72 ± 13	65 ± 10	p 0.01
Reserve heart rate beat/min	49 ± 24	54 ± 24	p 0.01
Max. Systolic AP mmHg	164 ± 34	161 ± 27	p 0.44

Table 5.

Comparative analysis of MOD-Bruce treadmill stress-tests based on ALT level.

In addition, the level of ALT ≤17 U/L was most significantly associated with (p 0.001) older age (≥67 years), body mass index (≤25.8) and female gender. When included in a multivariate regression analysis, hemoglobin≤100 g/L and ALT≤17 U/L independently of each other, and from other indicators, were associated with reduced exercise tolerance and thus with reduced cardiorespiratory suitability for cardiorespiratory training after CABG.

3.3 The role of the FIT treadmill index in the determination of cardiorespiratory fitness and the prediction of survival after CABG

In our study, 137 patients after CABG were followed up for 1 year. Before entering the cardiac rehabilitation program with the use of aerobic CRT, the average level of METs according to the BRUCE protocol was 6.3 ± 0.3. In 4-weeks of aerobic CRT, the average level of METs according to the BRUCE protocol was 8.3 ± 2.2 and exercise tolerance significantly increased by an average of 2.0 ± 1.2 METs. (p ≤ 0.05).

By risk category, before the start of aerobic CRT, 70% of our patients had a low probable risk of mortality (respectively, a high estimated survival rate) and 30% of patients had an intermediate probable risk of mortality according to the FIT-treadmill index. Considering the average age of our patients 68.5 to 8.3 years and an almost equal proportion of men and women (70 men, 67 women), the initial average of the FIT treadmill index was −69-59.5. After a 4-week course of aerobic CRT, the average FIT treadmill index was “-30.963.3”. Thus, the average improvement in the FIT treadmill index was 38,110.2 points. (p ≤ 0.05).

30% of patients who had an initially probable intermediate risk of mortality according to the FIT treadmill index (they also had a relatively high risk of adverse events based on the RARE scale>4), after a 4-week course of aerobic CRT using constant moderate intensity exercises, moved to the group with a low probable risk of mortality.

In a comparative analysis of the sensitivity, specificity, and predictive reliability of METs, the percentage of the maximum predictive heart rate (%Max. predictive HR) and the FIT-Treadmill index, the FIT-Treadmill index was statistically the most reliable (Figure 4). When analyzing the degree of improvement of the FIT-treadmill index after aerobic CRT, we identified a threshold value for an increase in FIT-Treadmill index score of 18.2 points with specificity of 76% (CI = confidence interval 68.1%–80.49%) and sensitivity of 68% (CI 52.9%–79.7%). Estimated survival rates were shown at 1 year.

Figure 4.

FIT treadmill index sensitivity and specificity in post CABG survival prediction.

Thus, the FIT treadmill index provides a quantitative measurement of cardiorespiratory fitness and allows to predict long-term survival. Obviously, participation in the cardiac rehabilitation program significantly improves the FIT-treadmill index.

3.4 Developed algorithms for the selection and risk stratification of patients for the efficient cardiorespiratory trainings after CABG

Conducted univariate and then multivariate regression analysis resulted in an algorithm for assessing the readiness and the risk of participation in aerobic CRT programs for patients after CABG.

Algorithm for the high level of readiness for aerobic CRT and for the low risk of adverse events after CABG in the presence of one of the following or more criteria determined the following variables:

• Uncomplicated postoperative course

• Exercise tolerance ≥7 METs

• < 4 points by RARE score.

• Absence of myocardial ischemia

• LV EF >50%

• Absence of high-grade ventricular arrhythmias according to Lown classification

• The level of the FIT treadmill index 1–100

• Blood ALT level ≥ 17 U/l

• The level of hemoglobin in the blood ≥100 g/l

Algorithm for the low level of readiness for aerobic CRT and an average risk of adverse events after CABG in the presence of one of the following or more criteria determined the following variables:

• The presence of angina pectoris

• Reversible deviations based on the results of a stress test on a treadmill

• Exercise tolerance 6–7 METs

• ≤ 4 points by RARE score.

• EF LV 45–50%

• FIT-treadmill Index level from −56,9 до −30,9 (≤0 to −100)

• Blood ALT level ≤ 17 U/l

• The level of hemoglobin in the blood ≤100 g/l

4. Discussion

It has been found that in trained people, regardless of their risk factor profile, mortality from cardiovascular events over a 30-year period is 50% lower than in untrained or poorly trained, i.e. physically inactive people [26]. Compared to less physically active men, the risk of cardiovascular events was shown to decrease progressively with increasing levels of cardiorespiratory fitness, especially among individuals with high and very high Agatson calcium index scores [27].

Patients who have undergone CABG have several limiting physical activity features such as deterioration of the function of external respiration with a decrease in respiratory volume, pain syndrome with little physical exertion, during breathing, decreased muscle strength due to immobilization. The presence of following “syndrome complexes” should be taken into account in the formation of physical rehabilitation measures: cardiac, post-sternotomy, respiratory, hemorheological, psychopathological, hemodynamic, metabolic and post-phlebectomy. This population of patients is recommended mobilization, including both active and breathing passive exercises. In the case of positive dynamics in the postoperative period, it is advisable to start with physical aerobic cardiorespiratory training. Cardiac rehabilitation including exercise training is indicated for all patients after CABG [28]. Our previous studies have shown positive effects of aerobic exercise training on metabolic and cardiorespiratory response in study group after CABG compared to control group without any training programs involved [29]. These positive effects were more obvious in high-intensity training group compared to moderate-intensity continuous training group [р < 0.01] in 4 weeks of trainings after CABG. Systematic physical training 3 times a week for 4–6 months in patients who have undergone CABG was associated with a significant increase in tolerance to physical activity up to 50% by 12 months and peak oxygen consumption, decrease of elevated heart rate (HR), improved daily physical activity and cholesterol concentration, level of high-density lipoproteins and improved quality of life.

Before embarking on a particular program of physical cardiac rehabilitation, a thorough assessment of the clinical and functional status of the patient is necessary, which should make it possible to create a risk stratification protocol: calculate the level of physical readiness for choosing the intensity of physical training, further planning a rehabilitation program; to assess the possible risks of various adverse events, cardiovascular morbidity and mortality in the long-term period after such operations.

Comparative analysis of 7 international protocols for cardiac risk stratification to conduct effective and safe training programs in adult patients with coronary artery disease did not allow to determine the best protocol for stratifying the risk of participation in training programs [19]. The analysis showed that none of these protocols was effective in such a prognosis and did not allow patients to be classified as at high risk of developing complications due to low positive predictive significance and low sensitivity (Table 1). The predictive significance of the protocols was greatest when used in the combination. It has been suggested that such encouraging results were due to a combination of the absence of potential risk predictors and the low incidence of serious complications during training programs. Although several protocols suggested using the risk stratification criteria associated with increased morbidity and mortality in the general population, it remained unclear whether the overall risk of cardiac events and the risk during training programs were the same phenomenon. Stratification criteria included factors associated with an increased risk of morbidity and mortality during physical training. However, the existence of multitude single-center protocols made it difficult to standardize the approach to the correct selection of patients for effective CRT programs.

When stratifying the risk of various complications, it is advisable and most effective to use both cardiac risk factors, as well as the assessment of non-cardiac comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease, cerebrovascular disease, and peripheral arterial disease.

The purpose of our research was to create a new algorithm for the selection of patients after CABG for effective and safe aerobic cardiorespiratory training. The results of aerobic cardiorespiratory training, as well as survival and morbidity, were evaluated within a year after surgery.

To determine the risk of adverse events associated with physical training, the international RARE scale was used, which considers heart rate, resting blood pressure, functional activity in METs, ischemic events according to the well-known classification of angina pectoris and ST-segment changes, left ventricular ejection fraction, and the presence or absence of arrhythmias.

The risk of adverse events associated with physical training in the study was extremely low, 0.8%, which is consistent with the data of other investigators. A high diagnostic reliability of the threshold value of the RARE scale ≥4 points in assessing the risk of developing adverse events due to physical training was shown.

The obtained protocol to determine the level of readiness to perform aerobic CRT after CABG included the following parameters: exercise tolerance in METs, RARE scale, FIT treadmill index, left ventricular ejection fraction, hemoglobin, and ALT levels.

The hemoglobin level ≤ 100 g/l did not serve as an obstacle to the onset of aerobic CRT, since it determined a reliably acceptable tolerance to physical activity on a 6-minute walk test and proved a significant restoration of the gap in cardiorespiratory capacity after a course of physical training.

The FIT-treadmill index was used to calculate long-term survival, as it is the powerful predictor of mortality with predictive power independent of age, gender, left ventricular ejection fraction and other traditional cardiovascular risk factors. It is easy to calculate. It is independent of symptoms and is not limited to electrocardiographic changes.

International risk stratification protocols for the selection of patients for the purpose of safe and effective CRT include neither the RARE scale, nor the FIT-treadmill Index, or laboratory parameters. Thus, a distinctive feature of our protocol is the ability to assess the logical pattern of the relationship of certain indicators with cardiorespiratory fitness and the possible risk of adverse events due to CRT, as well as the likelihood of assessing long-term survival in actively exercising and non-exercising patients. Groups of patients after CABG with low and high levels of readiness for physical cardiac rehabilitation were defined. It is necessary for the safe and effective performance of moderate- or high-intensity aerobic CRT in continuous or interval regimens.

Increasing the number of cardiac patients with concomitant pathology imposes the search and development of new criteria for efficient and safe cardiac rehabilitation after open heart surgery. The growing interest in this problem justifies the increase in the number of training programs offered. The proposed protocol for the management of patients after CABG contains a multiplicity of specific terms for monitoring the effectiveness of the measures taken, predictors by which the quality and efficiency of each individual case can be assessed.

Clinical implementation of our algorithms resulted in positive effects on metabolism, physiology, and hemodynamics of cardiovascular system. 96 patients with a high level of readiness for aerobic CRT and a low risk of adverse events were offered a transition from aerobic cardiorespiratory training of moderate intensity for 2 days to high-intensity interval aerobic cardiorespiratory training (HIIT). 41 patients with a low level of readiness for physical training and an average risk of adverse events were offered only moderate intensity continuous training (MICT). Aerobic cardiorespiratory trainings were carried out for 4 weeks under clinical observation.

In our study moderate intensity aerobic CRT was defined as a training when 60–75% of peak oxygen consumption or 60–75% of maximum training heart rate was achieved, and high-intensity aerobic CRT was defined as a training in which 80–85% of peak oxygen consumption or 80–85% of the maximum training heart rate was achieved.

As a result of aerobic CRTs, the indicators of peak oxygen consumption significantly improved - VO₂ (peak oxygen consumption), HR, power load and oxygen pulse (p < 0,001). VO₂, HR and power load significantly increased more in the HIIT group than in the MICT group (Table 6). In both groups, after aerobic CRT of high and medium intensity, there was a significant decrease in weight, body mass index (BMI), resting heart rate, a decrease in systolic and diastolic blood pressure, to a greater extent diastolic blood pressure, and an improvement in high-density lipoproteins (HDL) and a significant decrease in triglyceride levels, but the atherogenic coefficient did not change. From the baseline echocardiography parameters for the 4-week period of aerobic CRT, we observed a statistically significant decrease in the end-diastolic volume of the left ventricle (p 0.025) and an increase in LVEF (0.003), to a greater extent in the HIIT group. These observations confirm the positive effects of aerobic cardiorespiratory training on the physiology and hemodynamics of the cardiovascular system, lipid and carbohydrate metabolism.

	High intensity interval trainings (HIIT)			р
Variables	0 weeks	2 weeks	4 weeks	Inside group	Comparison between HIIT and MICT (p)
VO2(ml/kg/min)	23.5 ± 5.7	26.7 ± 5.7	30.6 ± 6.9	***a,b,c	*	Significant
HR (beat/min)	134 ± 21	140 ± 19	147 ± 18.2	***a,b,c	**	Significant
Power load (Wt)	154 ± 38.8	177 ± 45	192 ± 46.9	***a,b,c	*	Significant
RER	1.26 ± 0.12	1.27 ± 0.12	1.28 ± 0.11	NS	NS	NS
O2 pulse ml/beat/min	14.8 ± 3.6	16 ± 3.5	18.6 ± 3.5	***a,b,c	NS	NS
	Moderate intensity continuous trainings (MICT)
VO2(ml/kg/min)	22.4 ± 5.6	25.2 ± 6.2	27.8 ± 6.7	***a,b,c	*	Significant
HR (beat/min)	129 ± 21.1	133 ± 22.3	138 ± 21.5	***a,b,c	**	Significant
Power load (Wt)	145 ± 41	169 ± 47.9	180 ± 46.6	***a,b,c	*	Significant
RER	1.26 ± 0.11	1.26 ± 0.09	1.27 ± 0.09	NS	NS	NS
O2 pulse ml/beat/min	14.7 ± 2.9	15.9 ± 3.3	16.7 ± 3.2	***a,b	NS	NS

Table 6.

Comparative analysis of VO2, heart rate, power load, RER and O2 pulse.

^a variables in 2 weeks significantly differed from baseline.

^b variables in 4 weeks significantly differed from baseline.

^c variables in 4 weeks significantly differed from variables in 2 weeks of CRT.

*p < 0.05; **p < 0.01; ***p < 0.001; NS—nonsignificant, HR—heart rate.

О₂-pulse—it is the volume of O₂ that the blood absorbs with each contraction of the heart. О₂-pulse = (VO₂/HR). Normal values: 11–17 ml/beat/min.

RER respiratory exchange ratio—this is the ratio of O₂ consumed and CO₂ products. The RER reflects the level of transition from the aerobic supply zone to the anaerobic zone. At the time of transition from aerobic to anaerobic mode, the respiratory coefficient becomes equal to 1. The maximum value of the RER > 1 characterizes the maximum speed endurance.

The created algorithm for selecting patients allows safe and efficient usage of aerobic training programs of moderate and high intensity in continuous or interval modes, depending on the level of risk and the patient’s cardiorespiratory readiness. All this ensures the earliest possible start of cardiac rehabilitation programs, their continuity and duration.