Introduction
Currently, we observe an increase in the proportion of patients with chronic heart failure (CHF), in part due to improved life expectancy of patients with cardiovascular diseases (CVD). Decompensation of CHF is a main reason for hospitalization at cardiology departments, especially among patients over 65 years old [1]. E.g., according to the data provided by the USA and European countries, over a million patients are hospitalized annually for CHF. New algorithms for the patients with CHF management made it possible to increase the survival rate; yet, annual mortality rate in this group of patients is 7%, and severe decompensation requiring hospitalization reaches 17% [2]. Contrary to previously existing opinion, the more common form of CHF is CHF with preserved ejection fraction (CHFpEF). Each year, its share grows by one percent. Half of patients with CHFpEF are readmitted within six months after their discharge from the hospital. At the same time, mortality due to hemodynamic impairment among patients in this group reaches 30%. The combination of CHF with other diseases significantly worsens the prognosis for such patients [3, 4].
Difficulties in the diagnosis and treatment choice for CHF in patients with chronic obstructive pulmonary disease (COPD) substantiates an enlarged scientific interest in studying the cardiorespiratory state in recent years [5, 6]. Currently available data indicate that COPD affects 25%-42% of patients with CHF. Such patients are at increased risk of hospital readmission and death [7, 8].
There are common processes in the etiopathogenesis of both diseases: systemic inflammation, oxidative stress, and endothelial dysfunction [9, 10]. The main markers of systemic inflammation are proinflammatory cytokines that could be identified in the systemic circulation. Excessive activation of the synthesis of proinflammatory cytokines is pivotal in the development of CHFpEF (TNF-α, IL-1, etc.). Also, it leads to an increaseв activity of nitric oxide synthase. This negatively affects the cardiovascular system due to the direct toxic effect of nitric oxide on the myocardium, which leads to apoptosis and fibrosis of cardiomyocytes.
The study of the mechanisms of fibrosis and apoptosis in the myocardium led to the discovery of the suppression of tumorigenicity 2 (ST2) protein, a member of the interleukin 1 (IL-1) superfamily [11]. Various interactions between ST2 and IL-33 are described in the scientific literature: regulation of numerous biological processes, including the development and regulation of immune responses, along with the restoration of normal tissue homeostasis via supporting the wound healing process. However, IL-33/ST2 pathway could also lead to a loss of balance between the processes of systemic inflammation and tissue regeneration. It was established that its soluble form (sST2) can competitively bind to IL-33, suppressing its anti-fibrotic and anti-remodeling effects. Ultimately, a high level of sST2 in plasma leads to myocardial fibrosis and ventricular dysfunction [12].
Accordingly, high comorbidity of CHF and COPD, the difficulty of differential diagnosis of dyspnea in concomitant pathology, and an increased risk of adverse outcome substantiates further study of heart failure progression mechanisms, and improvement of diagnostic methods and treatment approaches in this category of patients. In recent years, three categories of patients with CHF were identified: with preserved, borderline, or reduced left ventricular ejection fraction (LVEF). Hence, it is of particular importance to study the effect of systemic inflammation on the clinical course, functional status and prognosis in patients with comorbid COPD and CHF, and different LVEF categories.
Objective – To evaluate the effect of COPD on the level of cytokines and the functional status of patients with CHF and different categories of LVEF.
Material and Methods
Study population
Of two thousand patients of the regional CHF register for Voronezh Oblast, the study included 240 patients 40 to 70 years of age with ischemic CHF (of which 134 were men and 106 were women, with a mean age of 71.4±8.4 years). The diagnosis of CHF was established on the basis of clinical guidelines for the diagnosis and treatment of acute and chronic heart failure [13]. The determination of the CHF functional class (FC) was carried out sensu 1994 New York Heart Association (NYHA) classification, based on the results of the six-minute walk test (6MWT). The patients were split among two groups: Group 1 (n=160) included patients with isolated CHF (86 men and 74 women, mean age = 73.2±8.8 years) who had no signs of lung diseases; Group 2 (n=80) comprised patients with a comorbid course of CHF and COPD, including 48 men (60.0%) and 32 women (40.0%), their mean age = 67.5±5.9 years. Patient characteristics are presented in Table 1. A phenotype with frequent exacerbations (twice or more annually) was detected in all included patients with COPD. They required the prescription of long-acting anticholinergics in combination with a long-acting β2-agonist. However, there were no indications for prescribing glucocorticosteroids to these patients. COPD was diagnosed based on GOLD COPD 2020 report [14].
Table 1. Patient characteristics
|
Indicator |
Group 1, CHF |
Group 2, COPD and CHF |
||
|
Subgroup 1 (n=69) |
Subgroup 2 (n=91) |
Subgroup 3 (n=36) |
Subgroup 4 (n=44) |
|
|
Women, n (%) |
32 (46.4) |
42 (46.2) |
14 (38.9) |
18 (40.9) |
|
Men, n (%) |
37 (53.6) |
49 (53.8) |
22 (61.1) |
26 (59.1) |
|
Age, years (М±σ) |
73.2±8.2 |
72.5±7.9 |
67.5±5.9 |
68.3±6.2 |
|
Body mass index, kg/m2 |
22.8±3.0 |
23.0±3.1 |
22.2±2.8 |
22.5±3.0 |
|
Ejection fraction, % |
53.4±3.2 |
45.6±7.1 |
53.8±3.5 |
46.1±7.5 |
|
Past history of myocardial infarction, n (%) |
3 (4.3) |
4 (4.4) |
2 (5.5) |
2 (4.5) |
|
Number of patients receiving i-ACE, n (%) |
52 (75.3) |
68 (74.7) |
27 (75.0) |
34 (77.2) |
|
Number of patients receiving ARBs, n (%) |
17 (24.7) |
23 (25.3) |
9 (25.0) |
10 (22.8) |
|
Number of patients receiving β-blockers, n (%) |
69 (100.0) |
91 (100.0) |
36 (100.0) |
44 (100.0) |
|
Number of patients receiving aldosterone receptor antagonists, n (%) |
19 (27.5) |
31 (35.1) |
11 (30.5) |
13 (36.3) |
According to the results of LVEF measurement, each of two groups (with an isolated course of CHF, and with a comorbid course of COPD and CHF) was divided into two subgroups. Patients with CHF, having borderline ejection fraction (40-50%) and reduced ejection fraction (<40%), were combined into reduced ejection fraction category (i.e., ejection fraction <50%). Subjects with an isolated course of CHF were allocated to Group 1 (n=160). Subgroup 1 included 69 patients with CHF and preserved ejection fraction (EF≥50%): CHFpEF. Subgroup 2 comprised 91 patients with reduced ejection fraction (EF<50%): CHFrEF.
Subjects with comorbid CHF and COPD were allocated to Group 2 (n=60). Subgroup 3 consisted of 36 patients with COPD and CHFpEF (EF≥50%), whereas Subgroup 4 included 44 patients with COPD and CHFrEF (EF<50%).
Exclusion criteria
The exclusion criteria for Group 1 were: lung diseases (including COPD and asthma), diabetes or using anti-diabetic medicines, chronic kidney disease (stages 3b and more severe), permanent form of atrial fibrillation, anemic syndrome; coxarthrosis, gonarthrosis and other diseases of the musculoskeletal system, which reduce physical activity; obesity (class II and more severe); malignant neoplasms, and diagnosis of chronic pulmonary heart disease. The exclusion criteria for Group 2 (patients with a comorbid course of CHF and COPD) were the same, except for the presence of COPD (there were no indications for administering glucocorticosteroids to these patients).
Patient examination
All participants were examined by both cardiologist and pulmonologist every week from the moment of inclusion in the study. This was used to control the absence of symptoms of CHF decompensation and COPD exacerbation. After 12 weeks, the study participants underwent 6MWT and standard examination. We employed comprehensive cardiorespiratory analysis and 6MWT to assess exercise tolerance [15]. The result was expressed in meters and compared with the proper six-minute walk distance: 6МWD (i). The formula for calculating 6MWD (i) for men was as follows: 6MWD (i) = 1,140 – 5.61 × BMI – 6.94 × age. For women, it was as follows: 6MWD (i) = 1,017 – 6.24 × BMI – 5.83 × age [16].
In addition to general clinical laboratory studies, enzyme immunoassays of blood were used to determine the levels of the N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (Hs-CRP), IL-1β, IL-6, and TNF-α. The following reagent kits were used: NT-proBNP ELISA Assay Kit from Biomedica, Austria; Human hs-CRP ELISA kit, IL-1 beta Human ELISA Kit, IL-6 Human ELISA Kit, Human TNF-alpha ELISA Kit from Vector-Best (Russia); The Presage® ST2 Assay kit from Critical Diagnostics, USA; and an automatic analyzer IMMULITE® 2000 (Siemens Diagnostics, USA). All patients underwent echocardiography (Echo) using EPIQ 5 Ultrasound Machine (manufactured by Phillips, USA), PureWave S5-1 transducer.
All patients received treatment in compliance with the guidelines for the CHF treatment [17]. All subjects signed an informed consent for voluntary participation in the study. The study was approved by the Ethics Committee of Voronezh State Medical University and was in compliance with the 1964 Declaration of Helsinki and its later amendments, or comparable ethical standards. It was carried out within the framework of the Grant No. MK-1776.2020.7, supported by the Russian Federation Council for Presidential Grants.
Statistical analyses
Statistical analyses were carried out using STATISTICA 10.0 software. Normality of data distribution was evaluated using Shapiro-Wilk and Kolmogorov-Smirnov tests. Continuous variables are presented in our article as M±SD (where M is the mean, and SD is the standard deviation). Comparison of unrelated groups was performed using Student’s t-test given the normal distribution. The null hypothesis was rejected at a significance level of p <0.05. All quantitative data were normally distributed.
Results
The obtained data demonstrated that CHFrEF was accompanied by an increased level of NT-proBNP, regardless of the presence or absence of COPD (Table 2). However, it should be noted that the combination of COPD and CHF in patients of Group 2 was accompanied by statistically higher level of NT-proBNP than in patients with isolated CHF: 1,512±229 ng/L vs. 1,004±174 ng/L; p=0.042.
Table 2. Comparison of laboratory vs. echocardiographic parameters in examined patients
|
Indicator |
Subgroup 1 (CHFpEF) |
Subgroup 2 (CHFrEF) |
р1-value |
Subgroup 3 (COPD and CHFpEF) |
Subgroup 4 (COPD and CHFrEF) |
р2-value |
|
NT-proBNP, ng/L |
813±127 ng/L |
1,171±191 |
<0.001 |
1,228±206 |
1876±254 |
<0.001 |
|
sST2, ng/mL |
23±9.4 |
32±13.2 |
<0.001 |
29±10.6 |
34±14.4 |
<0.001 |
|
LAVI, mL/m2 |
44.4±6.7 |
48.4±12.7 |
<0.001 |
46.4±7.2 |
49.8±13.0 |
<0.001 |
|
LVMI, g/m2 |
116.1±18.3 |
146.4±20.3 |
<0.001 |
110.1±16 |
140.4±19.1 |
<0.001 |
|
hs-CRP, mg/L |
3.7±0.62 |
2.6±0.59 |
<0.001 |
4.9±0.85 |
4.4±0.74 |
<0.001 |
Data are presented as mean ± standard deviation. CHFpEF, chronic heart failure with preserved ejection fraction; CHFrEF, chronic heart failure with reduced ejection fraction; COPD, chronic obstructive pulmonary disease; hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, NT-terminal fragment of pro-brain natriuretic peptide; LAVI, left atrial volume index; LVMI, left ventricular mass index, sST2, soluble suppression of tumorigenicity 2.
The content of sST2 was significantly higher in patients with CHFrEF vs. subjects with CHFpEF: 32±13.2 ng/mL and 23±9.4 ng/mL, respectively; p<0.001. The level of blood serum sST2 in Subgroup 4 (patients with COPD and CHFrEF) was 34±14.4 ng/L, which also significantly exceeded its value in patients of Subgroup 3 with COPD and CHFpEF (29±10.6 ng/L): p<0.001.
Comparison of echocardiographic parameters is also presented in Table 2. In patients with CHFpEF, mean values of the left atrial volume index (LAVI) and the left ventricular mass index (LVMI) were smaller than in patients with CHFrEF. Similar trend was observed in Subgroups 3 and 4: mean values of LAVI and LVMI were greater in the latter (p<0.001).
The hs-CRP content was measured to estimate the severity of endogenous inflammation. In patients with CHFpEF, the level of hs-CRP was 3.7±0.62 mg/L, while in patients with CHFrEF it was significantly lower: 2.6±0.59 mg/L (p<0.001). It was also lower in patients with COPD and CHFpEF (Subgroup 3) (4.9±0.85 mg/L) vs. Subgroup 4 subjects (4.4±0.74 mg/L): p<0.001.
All patients, regardless of their subgroup, had elevated levels of proinflammatory cytokines. However, significantly higher levels of IL-1β, IL-6, and TNF-α were detected in patients with a comorbid course of CHF and COPD. The results of determining proinflammatory markers in examined patients are presented in Figure 1.
Figure 1. Cytokine profile
We used a comprehensive cardiorespiratory analysis to assess the functional status of patients. The results obtained in the course of 6MWT in patients with COPD and CHF, regardless of LVEF, were numerically smaller than in patients with CHF (p1 = 0.04; p2 = 0.03). The explanation of these findings is a combination of both types of breathing disorders in patients with comorbid CHF and COPD, obstructive and restrictive. At the same time, in patients with an isolated course of CHF, we detected no significant obstructive breathing disorders.
Calculation of 6MWD/6MWD (i) ratio allowed establishing that in patients with CHF and COPD, this indicator was lower than in patients with CHF, regardless of LVEF. The results are presented in Table 2.
Heart rate (HR) before and immediately after 6MWT did not differ significantly between the subgroups. Furthermore, the device did not record the excess of submaximal values during the test in the subjects.
The SpO2 level was similar among the studied subgroups prior to the walk test. When assessing this parameter after the test, significantly lower values were recorded in patients with a comorbid course of CHF and COPD, regardless of LVEF category (Table 2). Exercise tolerance was also assessed via using the Borg Perceived Exertion Scale for assessing the severity of dyspnea after 6MWT. In patients with comorbid CHF and COPD (Subgroups 3 and 4), higher scores were registered, compared with subjects with isolated CHF (Subgroups 1 and 2) (Table 3).
Table 3. Comparison of 6MWT parameters in examined patients
|
Indicator |
Subgroup 1 (CHFpEF) |
Subgroup 3 (COPD and CHFpEF) |
р1-value |
Subgroup 2 (CHFrEF) |
Subgroup 4 (COPD and CHFrEF) |
р2-value |
|
6МWD, m |
301.5±153.5 |
264.6±120.6 |
0.04 |
251.5±183.5 |
202.4±130.2 |
0.03 |
|
6МWD, % from the proper value |
53.0±29.2 |
47.2±25.6 |
0.01 |
48.1±30.5 |
42.8±22.4 |
0.02 |
|
HR before test, beats per min |
76.1±15.2 |
77.8±17.3 |
0.18 |
86.1±15.2 |
87.8±17.3 |
0.16 |
|
HR after test, beats per min |
102.4±17.5 |
107.3±18.8 |
0.15 |
109.4±17.2 |
115.1± 4.8 |
0.15 |
|
SpO2 before the test, % |
97.9±2.0 |
97.5±2.1 |
0.12 |
95.2±2.4 |
94.9±2.6 |
0.26 |
|
SpO2 after the test, % |
95.5±3.0 |
93.3±3.1 |
0.001 |
94.1±3.3 |
91.2±2.5 |
0.001 |
|
Dyspnea sensu Borg, points |
2.41±0.17 |
3.22±0.29 |
0.01 |
3.83±0.32 |
5.19±0.37 |
0.001 |
Discussion
The manifestation of CHF means a poor prognosis for the patient, comparable to the prognosis for malignant neoplasms. The conventional diagnostic strategy includes an assessment of the structural and functional heart characteristics via ultrasonography, Doppler echocardiography and electrocardiography. Laboratory studies could serve an addition to these methods in such cases, including determination of natriuretic peptides, the level of which is associated with an increased load on the myocardium and left ventricular dysfunction (LVD). Consequently, the determination of Nt-proBNP concentration allows performing an assessment of left ventricular function, along with minimizing the use of invasive or expensive diagnostic tests.
A number of articles have been published on the effectiveness of determining the NT-proBNP content in patients with comorbid CHF and COPD. Determining the level of NT-proBNP in patients with COPD aged 65 years and older made it possible to detect CHF in primary care [18]. The authors used the threshold of NT-proBNP of ≥1,200 pg/mL. This helped diagnosing CHF in 5.6% of participating patients. Besides, there are published results implying that NT-proBNP is an independent predictor of death in COPD patients [19]. On the other hand, there is evidence that an increase in NT-proBNP allows suspecting CHF in patients with COPD: hence, such increase should be succeeded by further examination [20]. Similar results were obtained in our study: this biomarker did not lose its diagnostic value in the case of comorbid COPD and CHF. It was also noted that in patients with a combination of COPD and CHF, the level of NT-proBNP was statistically significantly higher vs. the patients with isolated CHF.
Of particular interest is the study of changes in sST2 level in response to the presence of COPD, CHF, or both. There are some studies indicating a more significant increase in this biomarker in CHFrEF vs. CHFpEF [21]. The data on changes in this indicator in COPD are scarce. The study by Thomas Muller et al. demonstrated that the level of sST2 was higher in patients with COPD than in patients with CHF [22]. However, this study did not include patients with a combined course of both diseases; therefore, we cannot unambiguously compare these results with ours.
A higher level of sST2 in patients with CHFrEF, in combination with more pronounced processes of hypertrophy and myocardial remodeling, which we described above, indicates that induction of sST2 can also be caused by mechanical overload of cardiomyocytes. Accordingly, an increase in the level of this biomarker may reflect myocardial stress, along with a change in the heart architectonics during the development of CHF and fibrosis.
Higher levels of IL-1β, IL-6, TNF-α, and hs-CRP (Figure 1) in patients with CHFpEF alone, as well as with CHFpEF and COPD (Subgroups 1 and 3), compared with Subgroups 2 and 4 with reduced EF, may reflect the significance of systemic inflammation contribution to the development and progression of heart failure. Furthermore, there are data indicating an increased risk of CHF in patients with COPD and increased CRP content [23].
The data obtained in our study suggested that the comorbid course of CHF and COPD was accompanied by a higher activity of proinflammatory cytokines (TNF-α, IL-1, IL-6), compared with isolated CHF. Previously, we revealed that in patients with COPD, a reduction in physical activity was apparently associated with multiple factors rather than resting lung dysfunction alone. For instance, in patients with COPD, a decline in lean body mass was often observed. It was a consequence of systemic inflammation and muscle atrophy due to low physical activity [8]. Therefore, it could be assumed that one of the components that reduce exercise tolerance in such patients is the activation of systemic endogenous inflammation, leading, among other consequences, to the muscle mass reduction.
Conclusion
CHF patients with pEF had higher levels of hs-CRP and proinflammatory cytokines, compared with patients with rEF. The combination of COPD and CHF amplified systemic inflammation and myocardial remodeling processes, determined by the level of NT-proBNP, as compared with an isolated course of CHF. A negative effect of COPD on the functional status of patients with CHF and different LVEF categories was established, which was manifested by lower 6MWT values and 6MWD/6MWD (i) ratio. An increase in the sST2 level was noted in patients with COPD and CHF, compared with patients with an isolated course of cardiac pathology. Further research is needed so that the obtained results would expand their diagnostic capabilities and assess the prognosis and effectiveness of pharmacotherapy in patients with comorbid COPD and CHF.
Financial support: The study was funded by the Grant No. MK-1776.2020.7 supported by the Russian Federation Council for Presidential Grants.
Conflict of interest: The authors declare no conflicts of interest.
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Received 12 April 2021, Revised 17 September 2021, Accepted 23 March 2022
© 2021, Russian Open Medical Journal
Correspondence to Roman E. Tokmachev. Phone: +79003003013; E-mail: r-tokmachev@mail.ru.
