Arterial hypertension with comorbid chronic obstructive pulmonary disease: relationship between tolerance to physical exercise and structural and functional state of the heart.

Arterial hypertension with comorbid chronic obstructive pulmonary disease: relationship between tolerance to physical exercise and structural and functional state of the heart. Burtniak T.Z., Potabasniy V.A., Fesenko V.I. The aim of the study was to establish the relationship between tolerance to exercise, oxygen saturation, and structural and functional cardiac status in patients with hypertension in combination with COPD. This study included 120 patients with primary arterial hypertension of stage I-II, grade 1, 2, and 3 in combination with COPD of grades 2 and 3 and clinical groups A, B, C, D, consisting group 1; group 2 – 30 patients with primary hypertension, and group 3 – 30 patients with COPD; group 4 – 30 practically healthy people representative by age and sex. Research methods included general clinical examination (collection of complaints, anamnestic data) and instrumental research methods: electrocardiography (ECG), echocardiography, measurement of ambulatory blood pressure (BP) profile (ABPM), spirometry, pulsoxymetry (SpO2), 6-minutes walking test (6MWT). On examination of 120 patients with stage I-II, grade 1 hypertension was established in 19 (15.8%), grade 2 was in 83 (69.2%) and grade 3 was in 18 (15%) patients, respectively. COPD in clinical group A was diagnosed in 10 (8.3%), B – in 51 (42.5%), C – in 18 (15%) and D in 41 (34.2%) patients, respectively. The most common was AH stage 2 with COPD in clinical group B – 35 (29.2%) cases and D – 31 (25.8%) cases. The 24-hour average systolic BP (SBP) in patients of the main group was 165 [144;178] mmHg, and the diastolic BP (DBP) was 103 [94;111] mmHg. The daytime average SBP was 160 [140;180] mmHg, and the DBP was 105 [93;117] mmHg accordingly. The night-time average SBP was 165 [155;175] mmHg, DBP – 100 [95;105] mmHg, heart rate (HR) – 83 [76;88] minutes, respiration rate (RR) – 21 [19;24] minutes. Decreases in index of chronotropic reserve (ICR) and the index of inotropic reserve (IIR) and load index indicate an increase in myocardial oxygen demand during exercise. There was an inverse correlation of IIR with SBP at rest (r= –0.42; p˂0.05) and a direct correlation with age (r=0.28; p˂0.05), which is significantly different from the control group. A direct correlation was found between the double product (DP) before and after exercise (r=0.43; p˂0.05), which indicated an increase in consumption of oxygen by the myocardium. We found a direct correlation between left atrium (LA) and the ratio of expiratory volume per 1 sec (FEV1) to the forced lung capacity (FEV) – FEV1/FVC (r=0.32; p˂0.05), which indicates the effect of the severity of bronchial obstruction on the level of left ventricular (LV) overload in patients with hypertension combined with COPD. The inverse correlation between thickness of the posterior wall of the LV (RVWT) and FEV1/FVC (r= -0.32; p˂0.05) indicates the contribution of disorders of bronchial patency and intrathoracic pressure with the level of BP to the development of concentric remodeling and LV hypertrophy. The inverse correlation between SV and COPD Assessment Test (CAT) (r= -0.32; p˂0.05) indicates an additional effect of COPD clinical severity on central hemodynamics in patients with hypertension. This relationship between the ventilatory and hemodynamic parameters is confirmed by the inverse

На умовах ліцензії CC BY 4.0 correlation of HR and FVC (r= -0.33; p˂0.05)), left ventricular internal dimension (LVEDD) of LV and CAT (r= -0.24; p˂0.05)), stroke volume (SV) and Modified British Medical Research Questionnaire (mMRC) (r= -0.42; p.00.05), CAT and pack years (r=0.33; p˂0.05), inverse correlation between CAT and mMRC and FEV 1 , FVC and FEV 1 /FVC (r= -0.40;p˂0.05 and r= -0.45; p˂0.05), respectively. Linear regression analysis showed that changes in SV LV, LVEDD and SpO 2 were dependent predictors of patient's worsening state according to CAT (p˂0.05). The direct correlation was established between the desaturation (ΔSpO 2 ) and ΔDP (r=0.48) and the inverse of ΔSBP (r= -0.29), 6MWT (r= -0.45), ICR (r= -0.34) and IIR (r= -0.29), which indicates a pronounced effect of hypoxemia on hemodynamics in patients with hypertension in combination with COPD. Comprehensive determination of cardiorespiratory reserve by 6-minute walk test, pulse oximetry and ambulatory blood pressure monitoring in patients with hypertension in combination with COPD makes it possible to establish disadaptation of the body to physical activity due to hypoxemia, decrease in the index of chrono-and inotropic reserves, which is an indication for administering appropriate therapy. In patients with hypertension combined with COPD, the degree of desaturation, stroke volume, enddiastolic parameters of the left ventricle, maximal size and volume of the left atrium, as well as remodeling of the left heart sections in the concentric direction can be considered as independent predictors of prognosis. The 6-minute walk test with desaturation can be used as an additional method of personalizing rehabilitation measures in patients with hypertension in combination with COPD.
The use of ambulatory blood pressure monitoring (ABPM) allowed us to evaluate the variability of blood pressure (BP), the effectiveness of antihypertensive therapy and to determine the predictors of cardiovascular mortality. Disorder of the daily profile of BP in patients with hypertension in combination with COPD is characterized by the predominance of "non-dipper" and "night-peaker" types, which increases the risk of damage to target organs and adversely affect the prognosis [9]. A direct correlation was found between hypoxemia, the grade of BP elevation, sympathetic activity and a correlation between a decrease in FEV 1 , desaturation, and variability in the BP night profile [4,18]. However, the question of the relationship between exercise tolerance and hypoxemia in patients with hypertension combined with stable COPD remains unclear. The answer lies in the plane of study of the cardiovascular system as a whole.
It is believed that impaired structural and functional status of the heart in patients with hypertension in combination with COPD is associated with the development of left ventricular hypertrophy (LV), its systolic, diastolic dysfunction and subsequent involvement of the right ventricular, which creates the basis for cardiac insufficiency, as a key mechanism for reducing exercise tolerance [4,15,19]. It is believed that impaired structural and functional status of the heart in patients with hypertension in combination with COPD is associated with the development of left ventricular hypertrophy (LV), its systolic, diastolic dysfunction and subsequent involvement of the right ventricle, which creates the basis for the development of heart failure (HF) as a key mechanism for reducing exercise tolerance [4,15,19]. The COSYCONET study [17] demonstrated that one of five COPD patients had cardiovascular pathology. The relationship between the LV remodeling profile, the ejection fraction (EF) stage and the chronic HF phenotype (CHF) was established [7,16].
The SCOTT study found that COPD patients had a more pronounced desaturation during physical activity due to hyperinflation, inadequate cardiac output, and increased peripheral oxygen extraction [11]. That is, the level of tolerance to physical activity, as a criterion of the general functional state, is determined as a whole by the cardiorespiratory system [2]. Therefore, in the combination of hypertension with COPD, it is important to identify the leading mechanism that limits the physical activity of the patient. Transient hypoxemia in patients with COPD associated with exercise, exacerbation, and increased bronchial obstruction at night adversely affect the cardiovascular system (CVS) [18].
The 6-minute walk test (6MWT) is the most affordable, low-cost method of study that does not require sophisticated equipment but correlates with maximal physical activity and oxygen absorption (maxVO 2 ) [2]. This test has a certain prognostic value and implies increased risk of hospitalization and mortality of patients with cardiovascular disease (CVD) [6].
The aim of the study is to establish the relationship between exercise tolerance, oxygen saturation, and structural and functional cardiac status in patients with hypertension in combination with COPD.

MATERIALS AND METHODS OF RESEARCH
The study included 120 patients with primary arterial hypertension of stage I-II, grade 1, 2, and 3 in combination with COPD of grades 2 and 3 and clinical groups A, B, C, D; group 2 -30 patients with primary arterial hypertension of stage II grade 2, and group 3 -30 patients with COPD of grade 2 and clinical groups -B 15 (50%) patients and D -15 (50%) patients and 30 practically healthy ageand the sex-representative people. The mean age of the patients in the main group was 58±7 years. Exclusion criteria are secondary AH, ischemic heart disease, heart failure above grade I according to the All-Ukrainian Association of Cardiologists (2017) and II Class according to New York Heart Association (NYHA), cerebral circulation disorders, chronic kidney disease, diabetes mellitus.
The structural and functional state of the heart was examined using Echocardiography by a standard technique. The studies were performed on a ZONAR Z.ONE PRO using a 3. To quantify the adaptive capacity of patients the double-product method (DP), or Robinson's index, DP reserve index DP= (HR˟SBP)/100 were used. Chronotropic cardiac function was determined using the index of chronotropic reserve (ICR, %): ICR = (load HR -rest HR)×100%/rest HR. Expected maximum HR -(exp max HR, beats/min) = = (208-0.7˟age). Expected CR -(exp CR) = = (exp max HR-HR)/HR. A chronotropic incom-petence (CI) was established at a level of XP ≤62%. The state of inotropic cardiac function during physical activity was determined by calculating the index of inotropic reserve (IIR, %): IIR = (load SBP -rest SBP)×100%/rest SBP. For analysis, the average daily blood pressure and heart rate before and after loading according to the ABPM data were used.
External respiration function was determined by computer spirometry "Pulmowind" "Sensorsystems" LTD. The calculated expiratory volume per 1 sec (FEV 1 ), the forced lung capacity (FEV) and their ratio (FEV 1 /FVC) were calculated. According to the Adapted Clinical Guideline 2019 and the GOLD 2019 Guideline, stratification of patients by COPD severity changed from an isolated assessment of the degree of bronchial obstruction by GOLD (FEV 1 /FVC and FEV 1 index) to a polyparametric integral assessment of the degree of shortness of breath, cough, amount of sputum, exercise tolerance and risk of exacerbation or death of COPD. In accordance with these parameters, according to the GOLD 2019 guidelines, criteria for individual COPD clinical groups were developed [8,15].
The Modified British Medical Research Questionnaire (mMRC) and the COPD Assessment Test (CAT) were used to assess patients' symptoms. Patients underwent standard pulse oximetry continuously while walking using a hand pulse oximeter, with desaturation criteria of SpO 2 ˂90% or ≥4%. Analysis and statistical processing of the material as performed using Excel (Microsoft Office 2016). Mathematical and statistical analysis of the results of the study was performed using the licensed program STATISTICA (version 10.0) using determination of mean values (M), standard deviation (SD), errors of mean value (m), (M±SD), and the interquartile range medians (Me [25-75%]). Univariate and stepwise multivariate logistic regression analysis was performed to determine the independent predictors of the combined endpoint. Significant differences were assumed to be p<0.05. All surveyed patients consented to the processing of personal data.
The 24 Table 2). According to our study, a direct correlation was found between HR and DP before loading (r = 0.31; p˂0.05) and HR and DP (r = 0.43; p˂0.05) after loading, indicating a change DP is due to the difference of the HR, not the SBP. Studies На умовах ліцензії CC BY 4.0 have shown that desaturation has a significant inverse correlation with FEV 1 , initial oxygen saturation, and a 6-minute walking distance, indicating a higher degree of airflow obstruction and lower SpO 2 tolerance at rest, which is confirmed by less time walking.
It was found that the ICR was 0.19 [0.14; 0.26], the inverse correlation between the HR before loading and the ICR (r= -0.47; p˂0.05), ICR and LA (r= -0,24; p˂0.05). ICR and RR (r=0.33; p˂0.05). There is an inverse correlation of IIR with SBP at rest (r= -0.42; p˂0.05) and a direct correlation with age (r =0.28; p˂0.05), which is significantly different from the control group. Decreases in ICR and IIR and load index indicate an increase in myocardial oxygen demand during exercise. A low increase in IIR in group 1 -0.08 [0.05;0.12] indicates a decrease in myocardial reserves and adaptive capacity of the functional coronary reserve of the organism, which exacerbates hypoxemia in patients with combined pathology of AH and COPD. CI is 0.56 [0.42;0.65], indicating a decrease in cardiac output due to tachycardia. An indirect correlation was found between SpO 2 and HR (r=-0.31; p˂0.05) between SpO 2 and RR (r=-0.36; p˂0.05), between SpO 2 and the average DBP (r=0.62; p˂0.05), between SpO 2 and the average daytime DBP (r =-0.52; p<0.05), SpO 2 and the average daytime DBP (r =-0.64, p˂0.05 ), which is explained by the response of peripheral vascular resistance to exercise.

Indicators of cardiorespiratory reserve in the main and control groups
External respiratory function in patients with hypertension in combination with COPD was  (Table 3), a significant increase in LVEDVI, RVWT, EF LV compared to the control and comparison groups was found. Concentric LV hypertrophy was most pronounced when combined with hypertension and COPD and was found in 26 (21.6%) patients, concentric remodeling was found in 40 (33.3%) patients, eccentric hypertrophy in 11 (9.2%) patients. In group 2, concentric remodeling was established in 11 (36.6%) patients, concentric LV hypertrophy in 10 (33.3%) patients, and eccentric LV hypertrophy in 1 (3.3%) patients. In group 3, concentric remodeling was established in 5 (16.6%) patients. The severity of LV hypertrophy in combined pathology is significantly higher than in hypertension and COPD without comorbidity, which is caused by hypertrophy and dilation of the right ventricle. The peculiarities of changes in the geometry of the LV in the combined diseases depend on both the level of blood pressure and the hypertrophy of the LV and the severity of hypoxia [19].
We found a direct correlation between LA and the FEV 1 /FVC (r=0.32; p˂0.05), which indicates the 19/ Том XXIV / 4 effect of the severity of bronchial obstruction on the level of LV overload in patients with hypertension combined with COPD. The inverse correlation between RVWT and FEV 1 /FVC (r=-0.32; p˂0.05) indicates the contribution of disorders of bronchial patency and intrathoracic pressure with the level of BP to the development of concentric remodeling and LV hypertrophy. The inverse correlation between SV and CAT (r= -0.32; p˂0.05) indicates an additional effect of COPD clinical severity on central hemodynamics in patients with hypertension. This relationship between the ventilatory and hemodynamic parameters is confirmed by the inverse correlation of HR and FVC (r= -0.33; p˂0.05)), LVEDD of LV and CAT (r= -0.24; p˂0.05)), SV and mMRC (r= -0.42; p.00.05), CAT and pack of years (r=0.33; p˂0.05), inverse correlation between CAT and mMRC and FEV 1 , FVC and FEV 1 /FVC (r= -0.40; p˂0.05 and r= -0.45; p˂0.05), respectively.

T a b l e 3
Structural and functional indicators of the heart according to Echocardiography The direct correlation was established between the desaturation (ΔSpO 2 ) and ΔDP (r=0.48) and the inverse of ΔSBP (r= -0.29), 6MWT (r= -0.45), ICR (r= -0.34) and IIR (r= -0.29), which indicates a pronounced effect of hypoxemia on hemodynamics in patients with hypertension in combination with COPD ( Linear regression analysis showed that changes in SVLV, LVEDD, and SpO 2 were dependent predictors of patient's state worsening according to CAT (p˂0.05) ( Table 5).
The inverse correlation between IP before and after loading and the size of the right atrium (r= -0.26; p˂0.05 and respectively r= -0.27; p˂0.05), PD and SWTD (r= -0,30; p˂0.05), between the increase in DP and PWTD (r= -0.29; p˂0.05), the increase in DP and LVESD (r= -0.24; p˂0.05), which indicates the systolic ability of the myocardium to respond to exercise in hypoxemia in patients with hypertension in combination with COPD.  The direct mean correlation was found between the load index and RV size (r=0.25; p˂0.05), between the load index and the LVEDD (r=0.37; p˂0.05), the LVEDD (r=0.35; p˂0.05) and SV (r=0.26; p˂0.05). According to the regression analysis, only the LVEDD and the LVEDD are independent indicators of load index, indicating the direct effect of hypoxemia on LV remodeling under load conditions at 6MWT. This, in turn, confirms the relationship between exercise tolerance and structural and functional state of the heart.

CONCLUSIONS
1. Comprehensive determination of cardiorespiratory reserve by the test of 6-minute walk, pulse oximetry and ambulatory monitoring of blood pressure in patients with hypertension in combination with COPD makes it possible to establish disadaptation of the body to physical activity due to hypoxemia, decrease in the index of chrono-and inotropic reserves, which is an indication for administering appropriate therapy.
2. In patients with hypertension combined with COPD, the degree of desaturation, stroke volume, end-diastolic parameters of the left ventricle, maximal size and volume of the left atrium, as well as remodeling of the left heart sections in the concentric direction can be considered as independent predictors of prognosis.
3. The 6-minute walk test with desaturation can be used as an additional method of personalizing rehabilitation measures in patients with hypertension in combination with COPD.