1. Relevance

Patients with breast cancer (breast cancer) may have a higher risk of cardiovascular disease (CVD) compared to the general population. Although modern cancer treatment methods, in particular, breast cancer (schemes based on anthracyclines, trastuzumab and radiation therapy (LT)), significantly reduce the risk of cancer recurrence and death, nevertheless they are associated with an increased risk of CVD [1-3]. According to literature data, chemotherapy (CT) based on anthracyclines and trastuzumab increases the risk of heart failure (HF) by 5 times compared to regimens without these components [4].

Another reason why patients with breast cancer may have a higher risk of CVD is that the risk factors (FR) of both diseases overlap, especially such FR as obesity and inactivity [5]. Patients with breast cancer may have a higher prevalence of FR CVD than in the general population. Pre-existing FR CVD was also associated with a higher risk of cardiotoxicity caused by cancer treatment [6-7].

Despite all the complexity and the areas being studied, the problem of women suffering from breast cancer in the aspect of the development of chronic heart failure (CHF), its early diagnosis and assessment of its severity, especially taking into account the cardiotoxicity of CT, is a very relevant and in-demand problem of modern cardio-oncology. In addition, due to the improvement of diagnostics in recent decades, there has been a rejuvenation of breast cancer. However, the question of the influence of age on the prognosis for breast cancer remains controversial. Some authors claim [8] that survival rates in breast cancer are comparatively lower for women under 40 than for older women, regardless of the histological type of and the stage of the process. Others write that breast cancer is the most common cancer among pregnant and lactating women and occurs in one case for every 3000-6000 pregnancies [9]. Nevertheless, in the literature we analyzed, we did not find data on the assessment of the influence of age on the severity of CHF in women suffering from breast cancer, which was the purpose of the presented scientific work.

2. Material and Methods

49 women suffering from breast cancer were examined, the average age of which was 55.1±8.7 years. Women over 70 years of age were not included in this fragment of the study. All patients suffered from breast cancer and CHF. All women included in the study, in addition to collecting and analyzing anamnestic data, conducted general clinical and laboratory studies, calculated body mass index (BMI). The severity of CHF was assessed by determining the functional class (FC II-III according to NYHA).

Instrumental studies included the removal and decoding of ECG in 12 standard leads with registration and analysis of cardiac arrhythmias (LDC), as well as EchoCG with the determination of indicators – end-diastolic (CDR, ml), end-systolic (CSR, ml) volumes of the left ventricle (LV), stroke volume (UO, ml) and left ventricular ejection fraction (LVLF).

LV myocardial mass (MMLH) was calculated using the "area – length" method, the results obtained were indexed in relation to the body surface area (the so-called indexed myocardial mass - IMLH). As the upper bound of the IMLF, a value for women of 104 g/cm2 was used, according to De Simone. The index of the relative wall thickness (OTC) in the diastole was calculated by the formula:

OTC = (TMJP + TSSLJ) / CDR,

where TMJP is the thickness of the interventricular septum, TSSLJ is the thickness of the posterior wall of the LV, CDR is the finite diastolic size of the LV. All indicators were calculated in cm. Based on the values of IMLJ and OTS, the following geometric types of LV were distinguished [7,8]:

– normal geometry (IMLJ≤N, OTS<0.45);

– concentric remodeling (IMLJ≤N, OTC≥0.45);

– concentric hypertrophy (IMLJ>N, OTC≥0.45);

– eccentric hypertrophy (IMLJ>N, OTC<0.45).

According to the results of the 6-minute walk test (TSHX), the functional class (FC) of CHF was determined by measuring the length of the distance traveled (DPD, m), as well as by the SHOCK scale.

3. Statistical Analysis

The data were described as mean ± standard deviation (M±SD) for the interval and quantity (%) for categorical variables. We used the chi-square criterion and the Fisher criterion for categorical variables. The Student's criterion was used for numerical variables. To assess the presence of links between the indicators, a correlation analysis was carried out with the calculation of the Pearson correlation coefficient. The value of p ≤ 0.05 was considered a statistically significant result.

Depending on the age, two groups were identified: group 1 – 15 women aged 30-50 years and group 2 – 34 women aged 51-70 years (since the patients were female, the premenopausal and menopausal periods served as the age selection category).

4. The Results of the Study

In the course of the study, it was found that, despite the different age categories, women of both the 1st and 2nd groups had comparable BMI values (Table.1). This was confirmed by the correlation analysis, which did not reveal any relationship between the age of women and BMI values (p=0.976; r=0.004; t=0.030). Nevertheless, the number of women with a BMI > 30 kg/m2 (i.e. with obesity) prevailed by 6.2% among group 1 individuals.

Table 1. General clinical characteristics of the compared groups of women

Analysis of central hemodynamic parameters showed that the patients of group 2 were characterized by higher values than the patients of group 1. In particular, SAD was higher by 12.0 mmHg; DAD was higher by 3.5 mmHg and HR was higher by 1.2 beats/min (all p>0.05), i.e. it can be said that the increase in age directly correlated with the development of GB (Fig. 1).

Figure 1. A graph of the correlation between age and the presence of GB in women with breast cancer. p=0,0000; r=0,557; t=4,598. (Note: on the X axis – the age of women in years, on the Y axis – under the number "0" - the absence of GB and under the number "1" - the presence of GB.)

When During the TSHC, it was revealed that the DPD in patients of group 2 was 30.8 m higher, and the number of SHOCK points was 0.5 units less than in group 1, however, the revealed differences did not reach the level of reliability (Table 1).

Assessment of concomitant pathological conditions found that in group 1, none of the patients had coronary heart disease (p < 0.0001), the presence of GB was only 20.0%, which was 65.3% less than in group 2 (p < 0.0001). Also, women of group 1 were more likely to have DM – by 4.5% and HRBS – by 10.4% (Fig. 2).

Figure 2. The occurrence of concomitant in the compared groups of women. (Notes: CHD – coronary heart disease; GB – hypertension; DM – diabetes mellitus; HRBS – chronic rheumatic heart disease; * - the reliability of differences in the compared groups at p < 0.0001.)

That is, the category of women "50+" was characterized by an increased level of central hemodynamic parameters, which was probably due to the prevalence of such cardiovascular pathologies as coronary heart disease and GB in them. On the contrary, the presence of DM was more often registered in women younger than 50 years, which, in turn, in combination with the BMI indicator (namely, the predominance of the number of patients with a BMI level > 30 kg/m2), indicates metabolic disorders at a younger age.

A comparative assessment of ECG characteristics did not establish significant differences between the groups. The durations of the QRS complex and the QT interval in group 1 were 9.1±1.0 ms and 34.4±2.6 ms, respectively; in group 2 – 9.3±1.1 ms and 34.2±2.8 ms (both p>0.05). Nevertheless, the presence of a pathological Q wave was noted in 13.3% of cases in women of group 1 and in 2.9% of cases in women of group 2 (p=0.452 and χ2=0.566). Cardiac arrhythmias (LDC) have also been reported: ventricular extrasystole (VE) was observed in 20.0% of women from group 1 and in 20.6% of patients from group 2 (p=0.736 and χ2=0.114) and supraventricular extrasystole (NE) in 13.3% and 17.6% of patients from groups 1 and 2, respectively (p=0.966 and χ2=0.002).

The data of the echocardiography revealed the following (Table.2): women of group 2, i.e. older than 50 years, had large heart volumes (BWW – by 10.9 ml; CSR – by 8.8 ml; UO – by 2.1 ml); better myocardial contractility (LVLF was higher by 6.3%) and greater values as MMLF (the difference was 38.7 gy.), and its indexed index (difference = 7.9 g/m2), in comparison with similar data of group 1 (all p>0.05). Despite the fact that the reference values of OTC were comparable, nevertheless, the number of women with OTC ≥ 0.45 units was higher in group 2 (32.4% vs. 20.0%).

Table 2. Echo CG-parameters of women with breast cancer depending on age

According to the indicators of LV and OTC, it was found (Fig. 3) that women of Group 1 mainly had either normal LV geometry (46.7%) or eccentric myocardial hypertrophy (40.0%). Patients of group 2 in most cases had an eccentric type of remodeling (52.9%); the presence of concentric hypertrophy was observed in 20.6% of cases, which was more than 3 (more precisely 3.07) times higher than the same indicator of group 1.

Figure 3. Geometric types of the left ventricle in the compared groups of women. (Notes: The data are presented as a percentage; LV – left ventricle.)

When conducting a correlation analysis between the LVLF – on the one hand and the number of CT courses taken – on the other hand, an inverse relationship was revealed, which, however, did not reach the level of reliability (p=0.137; r= -0.215; t= -1.510), i.e., the more CT courses a woman received, the worse the LVLF indicator became. The latter fact is probably due to the phenomenon of cardiotoxicity of CT, used as the main strategy for the treatment of cancer patients.

Thus, in women with breast cancer, despite their young age, the absence of obvious signs of coronary heart disease and a low percentage of GB (20.0%), even with preserved LV volume indicators, there was a more pronounced tendency to develop heart failure with the formation of an eccentric type of remodeling of the heart muscle, which emphasizes / proves more malignant (from the standpoint of the development of CVD) the course of the disease in women younger than 50 years.

From the laboratory data (Table.3) comparative analysis showed that low blood hemoglobin (Hb) levels were more often registered in women of group 1. Namely, Hb < 110 g/l was observed in 33.3% of cases in women younger than 50 years, which prevailed by 3.9% compared to the same indicator of group 2. Average values of the brain natriuretic peptide (MNUP) patients of group 1 had lower (the difference was 26.9 pg/ml) than women of group 2, as well as increased activity of this protein (MNUP > 300 pg/ml): 33.3% - in group 1 versus 50.0% - in group 2 (both p > 0.05),

Table 3. Laboratory data and oncological history

Despite the fact that the intergroup differences in the level of MNUP activity were not pronounced (all p > 0.05), nevertheless, the correlation analysis showed that women with breast cancer had a decrease in LVL as the MNUP grew (Fig. 4). This makes it possible to identify MNUP as an marker in the development of CHF in patients suffering from breast cancer.

Figure 4. A graph of the correlation between the values of MNUP and the level of LV PV. p=0,0000; r= -0,688; t= -5,541. (Note: the X-axis shows the digital values of LVEF in %, the Y-axis shows the MNUP indicators in pg/ml.)

From the data of the oncological history, it was found (Table 3) that in women younger than 50 years, the duration of the underlying disease was 0.7 years longer than in women of the "50+" category. This, in turn, contributed to the fact that the average number of chemotherapy courses (CT) in them was slightly higher (the difference was 0.2 units) than in patients of group 2, as well as the average dose of anthracyclines (the difference with group 2 was 13.2 mg).

Evaluation of side effects of CT according to the AS scheme in combination with found that in 8 (16.3%) of the entire sample of women, emetogenicity (high level of nausea and vomiting) occurred in the early stages of CT, while 6 women were from group 1 and 2 women from group 2 (p < 0.05), i.e. the majority of women who noted emetogenicity were younger than 50 years (Table 3). Direct analysis of patients who noted emetogenicity showed that 1 woman worked at a chemical plant and 7 women had severe toxicosis during pregnancy.

In our work, we tried to sum up markers that, in our opinion, could aggravate the phenomena of CHF in women suffering from breast cancer. These markers included:

1) age under 50;

2) BMI values ≥ 30 kg/m2;

3) The number of HT courses ≥ 10;

4) MNUP activity > 300 pg/ml.

In women with breast cancer, if the total value (∑) of all markers was equal to 0 points, we regarded it as a low risk of developing CHF; if ∑ = 1-2 points, it was assessed as an average risk; if ∑ ≥ 3 points, it was a high risk of developing CHF.

Mathematical calculations showed that 7 (14.3%) women had a low risk of developing CHF, while all of them were over 50 years old. The average risk of developing CHF was observed in 36 (73.5%) patients, of which 11 were from group 1 and 25 from group 2. A high risk of developing CHF was observed in 6 (12.2%) women (4 from group 1 and 2 from group 2). The average index ∑ in group 1 was 2.1±0.8 points and in group 2 1.2±0.8 points (p=0.000021).

The relationship of the severity of the course of CHF (FC CHF according to NYHA) with the selected markers during the correlation analysis established the presence of the following dependencies (all p > 0.05):

– there is an inverse correlation between CHF FC and the age of women (p=0.650; r= -0.066; t= -0.455), i.e. the younger the age, the higher the CHF FC;

– there is a direct relationship between CHF FC and BMI values (p=0.088; r=0.248; t=1.740), i.e. the higher the BMI, the higher the CHF class;

– there is a direct correlation between FC CHF and the number of CT courses (p=0.208; r=0.182; t= 1.274), i.e. the more CT courses, the harder the course of CHF;

– there is a direct relationship between the FC of CHF and the activity of MNUP (p=0.119; r=0.264; t=1.596), i.e. the higher the level of MNUP, the higher the class of CHF.

Thus, based on the above, our results indicate that for women with breast cancer, the greater the number of pathological markers, the harder it is FC HSN. This, in turn, contributed to the creation of a scale for assessing the severity of CHF in women suffering from breast cancer (Table 4).

Table 4. A scale for assessing the severity of CHF in women suffering from breast cancer

The scale developed by us for assessing the severity of CHF in women with breast cancer can be recommended for practical use by specialists in both oncology and cardiology, since it can improve the quality of examinations and therapeutic measures in this category of patients.

5. Discussion

Age, reproductive factors, personal or family history of breast diseases, genetic predisposition and environmental factors are associated with an increased risk of developing breast cancer. The peak incidence of breast cancer occurs during the postmenopausal period and accounts for up to 75% of all cases. On the contrary, in women younger than 35 years, the incidence of breast cancer is low – less than 5% of all cases [10]. This was confirmed in our study, where it was also revealed that among patients suffering from breast cancer, the number of women over 50 years old was more than 2 times more than the number of young women.

According to literature data, with obesity in women, changes in the function of the hypothalamic-pituitary system occur, hypothalamic control over the production of follicle-stimulating and luteinizing hormones of the ovary is disrupted. These disorders lead to amenorrhea, menorrhagia or prolongation of the menstrual cycle – which are risk factors for breast cancer [11]. In our study, the average BMI, regardless of age, was about 30.5 kg/m2, but the number of women with a BMI level > 30 kg/m2 among young women was 6.2% more than among women over 50 years old. In addition, women under the age of 50 had more cases of DM and HRBS, which, being systemic, could indirectly affect the hormonal background of our patients.

It is widely known that obesity is almost always combined with diabetes and hypertension. Studies show that the combination of diabetes and heart disease increases the risk of developing breast cancer by 2.2 times [12]. This is also in tune with our data. In particular, in the women we examined, the presence of GB occurred in 85.3% of cases among women over 50 years old and in 20.0% of cases in young patients, among whom, as mentioned above, DM was more often registered (13.3% in group 1 versus 8.8% in group 2) and BMI > 30 kg/m2.

Cardiotoxicity of chemotherapeutic drugs has a wide range of clinical manifestations: LV diastolic dysfunction (DD), HF, hypertension, vasospastic and thromboembolic ischemia, as well as various LDC [13-14]. Despite the variety of chemotherapeutic agents, anthracycline drugs remain the most commonly used in the treatment of breast cancer and are widely studied. Their use is associated with various mechanisms of cardiotoxicity development [15-16]. In relation to our study, this fact manifested itself as a decrease in the LVL index with the formation of an eccentric type of remodeling. According to the literature data, the cardiotoxic effect of CT is manifested by symptoms such as systolic or diastolic ventricular dysfunction with the development of dilated cardiomyopathy and a decrease in LV mass and wall, as well as possible cardiac rhythm and conduction disturbances, and a decrease in contractility [17], which also occurred in our patients.

Back in the 90s of the last century, the brain natriuretic peptide (MNUP), the most important peptide, was considered as the "Gold standard" for the prediction of CHF. The ventricles of the heart secrete it during overloads. Its secretion reflects changes in hemodynamics and signals LV dysfunction. An increase in its level indicates CH [18]. In our study, the activity of MNUP was more pronounced in women over 50 years of age. In general, according to the sample, an increase in MNUP was reliably associated with a decrease in LVL, which allows us to assert that it is informative in assessing the severity of CHF even in patients with breast cancer and to single it out as an unfavorable marker.

Thus, our study shows that in women suffering from breast cancer, when assessing the risk of developing CHF, it is necessary to pay close attention to the study of age-related features and a combination of risk factors such as BMI, MNUP activity and the number of CT courses.

6. Conclusions

The category of women "50+" was characterized by an increased level of indicators of central hemodynamics, which was probably due to the prevalence of such cardiovascular pathologies as coronary heart disease and GB. On the contrary, the presence of DM was more often registered in women younger than 50 years, which, in turn, in combination with the BMI indicator (namely, the predominance of the number of patients with a BMI level > 30 kg/m2), indicates metabolic disorders at a younger age.

In women with breast cancer, despite their young age, the absence of obvious signs of coronary heart disease and a low percentage of GB (20.0%), even with preserved LV volume indicators, there was a more pronounced tendency to develop heart failure with the formation of an eccentric type of remodeling of the heart muscle, which emphasizes / proves a more malignant (from the standpoint of the development of CVD) course of the disease in women younger than 50 years.

Despite the absence of intergroup (depending on age) differences in the level of MNUP activity (all p > 0.05), nevertheless, the correlation analysis showed that in women with breast cancer, as the MNUP grew, there was a decrease in LVL, which makes it possible to identify MNUP as an unfavorable marker in the development of CHF in patients suffering from breast cancer.

Age younger than 50 years; BMI values ≥ 30 kg/m2; the number of CT courses ≥ 10 and MNUP activity > 300 pg/ml – can be considered as unfavorable markers in assessing the risk of developing and severity of CHF in patients with breast cancer.