INTRODUCTION

Over the years, heart failure remains one of the most common and prognostically unfavorable pathological conditions [1] and the final stage of virtually all heart diseases. It is predetermined not only by its overload but also by the complex interaction between genetic, neurohumoral, metabolic, inflammatory and other factors having a direct impact on the heart [2]. Despite the fact that at present, the survival of patients with chronic heart failure (CHF) has improved, primarily due to modern medication, nevertheless the mortality rate remains very high [3]: more than 30% of patients die within 5 years of diagnosis [4]. That is why the search for pathogenic and prognostic factors influencing the duration of CHF remains relevant. One of these factors is obesity, which is recognized as a non-infectious pandemic of our time. According to literature data, in 2014 about 1.9 billion adults worldwide were overweight and more than 600 million were suffering from obesity [5].

However, the effect of obesity on the course of a cardiovascular disease is ambiguous. The phenomenon described in literature data is known as the “paradox of obesity” [6], which suggests that overweight patients with cardiovascular disease have a better prognosis than those with normal body weight [7]. Another factor that has an effect on the course and may worsen the condition of patients with chronic heart failure is endogenous intoxication syndrome (EIS) characterized by a complex of metabolic, morphological and functional disorders in various vital organs and systems of the body [8]. The influence of each of these factors separately on the course of CHF is actively discussed in the literature. However, in practice, we often encounter a situation where several factors simultaneously influence the course of the disease.

Prognosis of the CHF course in clinical practice, depending on the body mass index and the degree of endogenous intoxication has not yet been reflected in the available literature, which determined the relevance and feasibility of our study.

THE AIM

The aim of our study was to determine the frequency of complications in patients with CHF, provided the combined influence of different BMI and endogenous intoxication levels.

MATERIALS AND METHODS

A complete clinical examination was performed in 58 patients (41 (70.6%) men and 17 (29.4%) women) with CHF. The formation of clinical groups of CHF was performed in accordance with the classification of the New York Heart Association (NYHA, 1964), considering the guidelines of the Ukrainian Association of Cardiology (2017), defining the clinical stage of CHF, its type and the FC in accordance with the Ministry of Health of Ukraine Order of 03.07.2006, No. 436. The study was based on the ethical principles for research (Helsinki Declaration). The study was approved by the Ethics Committee of the Lviv National Medical University named after Danylo Halytsky. All participants have signed an informed consent form.

The main cause (84.5%) of CHF was coronary heart disease, in 15.5% – chronic rheumatic heart disease. The most common form of coronary artery disease was angina pectoris (69.1%). A permanent form of atrial fibrillation was observed in 29.1% of patients, and 15.5% had diabetes mellitus. In addition to standard clinical examinations, the determination of body mass index (BMI), N-terminal brain fraction of natriuretic propeptide by qualitative method (CITO TEST NT-proBNP, Pharmasco), endogenous intoxication evaluation by the level of medium-weight molecules (MWM254) spectrophotometrically in the ultraviolet region of the spectrum by N.I. Gabrielyan et al. (1985), leptin determination by means of enzyme-linked immunosorbent assay using “DRG Leptin ELISA” reagents (Germany) were performed. The structural-functional parameters of the heart were determined using the ultrasound machine Aloka SSD-500 (Japan) in accordance with the standard technique.

Statistical processing of the results was carried out using the methods of variation statistics “Statistica 6.0” (USA), the correlation analysis was performed by the Kendall method. Nonparametric indicators were compared using the Mann-Whitney criterion and were represented as a median [lower; upper quartile]. Prognosis of the CHF severity and survival analysis were performed by Kaplan-Meyer: the cumulative survival rate at 24 months of follow-up with the evaluation of significance by Gehan-Wilcoxon test and Cox test F-criteria were estimated. Re-hospitalization due to decompensation of CHF or death of the patient were considered an event.

RESULTS AND DISCUSSION

In order to evaluate the combined effect of the body mass index (BMI) and endogenous intoxication syndrome on the CHF prognosis, we have randomized the examined patients into 4 groups: 1st group (6 patients, 5 men and 1 woman) – patients with normal body mass and MWM less than the median (< 0.67 СU), 2nd group (7 patients, 6 men and 1 woman) with normal body mass and MWM> 0.67 CU, 3rd group (22 patients, 15 men and 7 women) – patients with excessive body weight and obesity and MWM <0.67 CU, 4th group (23 patients, 15 men and 8 women) – overweight and obese patients and MWM> 0.67 CU.

Survival analysis in the studied groups of patients indicates that the incidence of non-event survival was highest in patients of the 1st group and was 100%, while in the 2nd group it was 25.0%, in the 3rd – 76.2% and the 4th – 62.5% (table I, fig. 1). The worst CHF prognosis was found in patients with normal body mass against the background of a severe syndrome of endogenous intoxication. In this group, 75% of patients were reported to have complications or death of a patient, that significantly differed from the group of patients with lower MWM levels and normal body weight (Gehan-Wilcoxon criteria p = 0.01), overweight and obese patients with MWM < 0.67 CU (Cox test F-criterion, p = 0.008, Gehan-Wilcoxon test p = 0.02) and even patients with excess body weight, obesity and MWM > 0.67 CU (Cox F-criterion p = 0.04 and Gehan-Wilcoxon criterion p = 0.1).

The best prognosis was observed in CHF patients with normal body weight and low MWM <0.67 CU.

An analysis of clinical, laboratory and instrumental data on their correlation with BMI and MWM was performed. Our study had revealed that a number of parameters were dependent on the level of MWM and BMI. Partially better prognosis in obese patients may be explained by the fact that patients with concomitant obesity (groups 3 and 4) were significantly younger than the patients with normal body weight (groups 1 and 2) (Table II).

Patients with the highest percentage of non-event survival had the lowest levels of fibrinogen, the highest levels of systolic and diastolic pressure, less pronounced left ventricular hypertrophy, the lowest degree of endogenous intoxication and the highest levels of triglycerides in the blood.

According to the results presented in the table, the worst prognosis in patients of the 2nd group may be due to the fact that in patients with normal body mass, in the presence of severe endogenous intoxication, hypoleptinemia was observed. The level of leptin in such patients was 0.48 ng/ml, compared with 3.99 ng/ml, provided the excess body mass and expressed EIS (4th group), 3.6 ng/ml in patients with normal body mass and low levels of intoxication (1st group), and 10.7 ng/ml in patients with excess body weight and obesity and low degree of endogenous intoxication (3rd group).

According to the literature data [9], the synthesis of leptin is suppressed by the sympathoadrenal system. The leptin deficiency impairs the regulation of lipids in peripheral organs and results in the intracellular accumulation of lipids by reducing the synthesis of fatty acids and triglycerides, which ultimately causes lipotoxicity and apoptosis. In our study, this is confirmed by the low level of TG in patients of the 2nd group, in which the TG level is the lowest and is 78.8 mg/dl (significantly lower than in patients of the 1st group p1-2 = 0.008, 3rd group p2-3 = 0.005 and 4th group p2-4 = 0.01). As for triglycerides, they are non-specific acceptors of toxins, and in conditions of hypotriglyceridemia, the body becomes more sensitive to endotoxins, which is how negative prognosis can be explained. In patients with obesity and without intoxication, the level of leptin is increased to 10.7 ng/ml, and in patients with intoxication, apparently decreases due to the activation of the sympathoadrenal system and its level approaches normal, 3.99 ng/ml. It alleviates the cardiotoxic effects of hyperleptinemia in obese patients and is associated with a better prognosis.

The level of leptin depends on many factors – such as gender, body weight, hormonal background and the influence of environmental factors [9]. Most researchers affirm that CHF is accompanied by an increase in the blood level of leptin [10, 11], which has a deleterious effect on the myocardium, vascular wall, and renal tissue by activating the transforming growth factor and receptors to it. Although, according to other data, in severe CHF its content is reduced [12]. According to some studies [13], the level of leptin in patients with CHF was 9.2 ± 7.5 ng/ml. In our study, CHF patients had a blood leptin level of 6.94 ng/ml. The level of leptin directly correlated with the magnitude of both systolic blood pressure (τ = 0.4; p = 0.005) and diastolic blood pressure (τ = 0.3; p = 0.03), hemoglobin (τ = 0.3; p = 0.02), blood glucose (τ = 0.4; p = 0.008), relative interventricular septum thickness (τ = 0.4; p = 0.04), cholesterol (τ = 0.5; p = 0.001), HDL cholesterol (τ = 0.4; p = 0.02), LDL cholesterol (τ = 0.4; p = 0.004), TG (τ = 0.4; p = 0.004). Consequently, the increase in the level of leptin will be associated with arterial hypertension, increased blood glucose levels and lipid metabolism disorders, which is particularly unfavorable for the CHF course.

Thus, the discrepancies in the indicator of non-event survival of patients with CHF with different BMI, obviously, cannot be explained by varying degrees of systolic dysfunction, since by the LV EF magnitude patients with the best prognosis did not differ significantly from those with the worst prognosis. In our opinion, the severity of endogenous intoxication, in particular, may be the determining factor affecting the survival rate and the incidence of complications in such cases. The inverse correlation between BMI and the level of MWM in the blood (τ = -0.2, p = 0.01) serves in favor of this opinion.

In addition, the controversial issue about the normal level of leptin in patients with CHF should be considered in the context of the underlying disease, taking into account all factors that have an effect on it, in particular, endogenous intoxication syndrome.

CONCLUSIONS

The worst prognosis was observed in patients with normal body mass on the background of the expressed syndrome of endogenous intoxication, and the best – provided a normal weight and low level of intoxication.

Patients with CHF should have their leptin level evaluated. An increase in its level was associated with arterial hypertension, an increase in blood glucose levels and lipid metabolism disorders.

The worst prognosis was observed in patients with the combination of hypoleptinemia with severe endogenous intoxication.

Table I. The incidence of non-event survival in patients with CHF depending on the MWM and body weight

Group

Proportion of patients

with reported event

without reported event

1

100 %

2

75 %

25.0 %

3

23.8 %

76.2 %

4

37.5 %

62.5 %

Figure 1. Survival curves of patients with CHF for 24 months depending on BMI and blood MWM

Note: The difference is significant between patients in 1st and 2nd groups (Gehan-Wilcoxon p = 0.02),

2nd and 3rd groups (Cox F-criterion p = 0.008, Gehan-Wilcoxon p = 0.02),

2nd and 4th (Cox F-criterion p = 0.04).

Table II. Clinical and laboratory parameters in patients with CHF depending on BMI and MWM

Parameter

1st group

2nd group

3rd group

4th group

Р

Age, years

79 [74; 83]

78[67; 81]

64 [50; 73]

67[49; 73]

P1-3=0.006

P1-4=0.007

P2-3=0.02

P2-4=0.04

Cardiovascular risk factors

AH, % (n)

66.6 (4)

28.6 (2)

81.8 (18)

56.5(13)

Р2-3=0.009

Diabetes mellitus, % (n)

16.6 (1)

0 (0)

18.1 (4)

17.3 (4)

Р2-3=0.03

Р2-4 =0.03

Heart failure cause

CHD, % (n)

100% (6)

100% (7)

72.7%(16)

86.9 (20)

P1-3=0.008

P2-3=0.008

Chronic rheumatic heart disease, % (n)

0

0

27.3 (6)

13.1 (3)

P1-3=0.008

P2-3=0.006

Clinical laboratory parameters

Incidence

of EF< 30%

16.7 (1)

28.6 (2)

13.6(3)

13.0(3)

p>0.05

NYHA I, %, (n)

16.7 (1)

14.3 (1)

22.7 (5)

13.0 (3)

p>0.05

NYHA II, %, (n)

50 (3)

14.3 (1)

54.6 (12)

43.5 (10)

P2-3=0.02

NYHA III-IV,

%, (n)

33.3 (2)

71.4 (5)

22.7 (5)

43.5 (10)

P2-3=0.01

Systolic arterial pressure, mm Hg

160[140;180]

110[110;125]

145[130;170]

140[130;160]

P1-2=0.001

P2-3=0.0008

P2-4=0.002

Diastolic arterial pressure, mm Hg

90[90;100]

75[70;80]

90[85;100]

87[77;95]

P1-2=0.01

P2-3=0.0007

P2-4=0.04

Fibrinogen, g/L

2.4 [2.4; 2.9]

2.7 [2.6; 3.3]

3.5 [2.8; 4.4]

3.3 [2.4; 3.8]

P1-3=0.04

White blood cells, *109/L

7.9 [7.3;8.4]

6.3 [4.8;8.7]

7.8 [6.5; 8.5]

8.2 [6.7;9.8]

Р>٠.05

ESR, mm/hr

11 [8;12]

7 [4;15]

13.5 [5;20]

7 [5;20]

Р>٠.05

Lymphocytes, %

21 [20;24]

17 [14;33]

24 [20;30]

21 [17;26]

Р>٠.05

RV, cm

2.43 [2.25; 3.19]

2.67 [2.40; 3.62]

2.47 [2.24; 2.89]

2.60 [2.50; 3.34]

Р>٠.05

IVST, cm

1.18 [0.83; 1.21]

1.26 [1.21; 1.44]

1.42 [1.21; 1.58]

1.40 [1.29; 1.70]

P1-4=0.01

P2-3=0.01

LVPWT, cm

1.2 [1.1; 1.2]

1.4 [0.6; 1.4]

1.4 [1.3; 1.6]

1.2 [1.2; 1.3]

P1-3=0.02

P1-4=0.04

LVEDD, cm

5.52 [4.86; 6.77]

6.07 [5.17; 6.18]

5.44 [5.30; 6.30]

5.99 [5.09; 6.50]

Р>٠.05

EF, %

52.5 [33.0; 63.0]

36.5 [27.9; 55.5]

57.0 [39.0; 62.0]

44.5 [41.0; 64.0]

Р>٠.05

MWM, CU

0.4 [0.4; 0.5]

0.9 [0.6; 1.1]

0.5 [0.3; 0.6]

0.9 [0.7; 1.2]

P1-2=0.001

P1-4=0.000004

P2-3=0.000001

HDL, mg/dl

42.1 [35.9; 59.6]

47.1 [24.7; 80.0]

44.1 [38.6; 51.0]

36.3 [28.6; 46.8]

Р3-4=0.04

LDL, mg/dl

118.3 [67.8; 148.4]

97.8 [64.9; 112.5]

96.6 [84.3; 116.7]

84.6 [68.4; 120.6]

Р>٠.05

TG, mg/dL

155.1[100.9; 190.0]

78.3 [51.3; 95.4]

120.4 [87.6; 192.0]

132.7 [77.8; 159.2]

P1-2=0.008

P2-3=0.005

P2-4=0.01

Leptin, ng/mL

3.6 [2.2; 5.5]

0.48 [0.15; 0.81]

10.7 [3.8; 18.5]

3.99 [2.5; 7.1]

P2-3=0.02

L-arginine, µg /ml

10.5 [2.5; 12.8]

7.7 [5.1; 10.1]

6.6 [5.6; 9.1]

8.6 [6.4; 11.0]

Р>٠.05

*RV – right ventricle dimensions, IVST – interventricular septum thickness, LVPWT – thickness of left ventricular posterior wall, LVEDD – left ventricle end-diastolic diameter, EF – ejection fraction, HDL – high-density lipoprotein cholesterol, LDH – low-density lipoprotein cholesterol, TG – triglycerides