THE EFFECT OF IVABRADINE AND ω-3 POLYUNSATURATED FATTY ACIDS ON THE FIBRONECTIN PLASMA LEVELS IN PATIENTS WITH HEART FAILURE

Chronic heart failure (HF) is a highly prevalent chronic pathological condition with high morbidity and mortality rates. The cost for HF treatment is 2% of the national health expenditures each year. Fibronectin (Fn) has a crucial role in the process of tissue-specific morphogenesis and cell differentiation in embryogenesis; it stimulates fibroblasts and different growth factors during wound healing and tissue reparation. The aim of our study was to assess the possible effects of Ivabradine and ω-3 polyunsaturated fatty acids on the fibronectin plasma level in patients with heart failure. 357 Patients with ischemic HF and the sinus rhythm were observed. In accordance to treatment regimens all patients were divided into four groups: group I – basic treatment; group II – basic treatment and Ivabradine; group III – basic treatment and PUFA; group IV – basic treatment with Ivabradine and PUFA. The fibronectin levels were measured by ELISA method. The average value of the Fn concentration in HF patients was 1.25 times higher than in the control group (p<0.05). In patients with basic HF treatment the tendency to the Fn plasma level decrease (p>0.05) was observed. In the group with additional prescription of Ivabradine the concentration of this protein in the blood decreased by 14.5% (p<0.01). The same situation was observed in the group with additional use of PUFA – by 11.1% (p<0.05). In group IV the plasma concentration of Fn decreased by 12.9% (p<0.05). Thus, Ivabradine and ω-3 polyunsaturated fatty acids, either alone or in combination, decrease the plasma levels of fibronectin in patients with heart failure, and it shows a pronounced cardioprotective effect.

Chronic heart failure (HF) is a highly prevalent chronic pathological condition with high morbidity and mortality rates. The prevalence of HF is 1% to 2% in the general population worldwide and at least 10-20% among the age group of 75 years and older [7]. The cost for HF treatment is 2% each year [11].
Fibronectin (Fn) has a crucial role in the process of tissue-specific morphogenesis and cell differentiation in embryogenesis; it stimulates fibroblasts and different growth factors during wound healing and tissue reparation [10]. The experimental investigations conducted demonstrated the importance of this protein in HF progression [4].
According to the current recommendations the main aim of treatment of HF patients is reduction of symptoms and signs, prevention of hospital admissions and increased life expectancy [5,7].
Heart rate is an important factor of pathogenesis of coronary artery disease and HF. It is a modifying risk factor [6]. There are a lot of mechanisms of increase of a cardiovascular risk due to the high heart rate: oxygen demand, acceleration of atherosclerosis, and possibility of atheroma rupture [3]. Thus, the heart rate reduction is one of the priority targets in CAD and HF treatment. Ivabradine is a representative of a new class of medicines with reduction effects on the heart rate. It is approved for HF management. There are no data of influence of this medicine on some components of the extracellular matrix.
Taking into account the role of inflammation in HF pathogenesis, ω-3 polyunsaturated fatty acids (ω-3 PUFA) are referred to the drugs used for its treatment. These acids affect the lipid metabolism and various factors of the inflammatory process, thus improving the prognosis of patients with cardiovascular diseases.
The aim of our study was to assess the possible effects of Ivabradine and ω-3 polyunsaturated fatty acids on the fibronectin plasma level in patients with heart failure.
Materials and Methods 357 Patients with ischemic HF and the sinus rhythm were observed. In accordance to treatment regimens all patients were randomized as follows: group I (89 patients) -basic treatment; group II (91 patients) -basic treatment and Ivabradine (Coraxan, Les Laboratoires Servier Іndustrie, France) -5 or 7.5 mg twice a day; group III (90 patients) -basic treatment and PUFA (Omacor, Abbott Laboratories GmbH, USA) -1000 mg per day; group IV (87 patients) -basic treatment with Ivabradibe and PUFA in similar doses. All patients were examined before and after 6 months of treatment. The control group was 30 practically healthy persons. The study was performed in accordance with the Helsinki Declaration and Good Clinical Practice Guideline. The study was approved by the local ethics committee, and the written informed consent was obtained from all patients.
The fibronectin levels were measured by ELISA method with "Fibronectin ELISA Kit" (Technoclone GmbH, Austria).
Statistical analysis was performed using a "Statistica for Windows 12.0" programme (StatSoft, Tulsa, OK, USA). Difference was considered significant at p<0.05.

Results and Discussion
The average age of the patients with HF examined was (67.98±12.06) years. The average value of the Fn concentration in HF patients was 1.25 times higher than the same value in the control group: (259.55±7.88) μg/ mL versus (207.56±13.62) μg/mL (p<0.05).
The Fn plasma levels elevation is one of the factors of atherosclerosis progression. This protein can be compared with a double-edged sword, which on the good edge, promotes the formation of a thick fibrous cap, but on the bad edge, expands the ECM, resulting in more atherogenic lipoprotein retention. This unfavourable consequence alone would result in infiltration of inflammatory cells and plaque progression [9].
Some trials showed the influence of activated reninangiotensin-aldosterone system (RAAS) on elevation of Fn in plasma [1]. In our opinion, the use of RAAS blockers as components of HF management causes a decreasing trend in this parameter.
The effect of ω-3 PUFA on the Fn levels probably occurs via its anti-inflammatory mechanisms. Some researchers suppose that Fn is a protein of the acute phase of inflammation, which takes an active part in the processes of nonspecific immune response [12].
The mechanism of the effect of Ivabradine on the Fn levels reduction in the blood remains unclear. It is obvious that it occurs by two main ways: first -via the heart rate reduction (which is an important factor of myocardial fibrosis [8]); second -via anti-inflammatory effects of Ivabradine (some experimental results showed the decrease of the concentration of interleukin-6, tumour necrosis factor -α and protein of chemotaxis of macrophages-1in the myocardium [2]).