Erythropoietin (EPO) is a glycoprotein hormone synthesized predominantly in the kidneys and stimulates the proliferation and maturation of erythroid cells in the bone marrow. EPOs have recently become very popular with their anti-inflammatory, anti-oxidant, anti-apoptotic and angiogenic effects, as well as the treatment of anemia due to chronic renal failure, where they are frequently used [24]. However, the number of studies investigating the cardiac effects of EPO, which is known to be used by athletes for doping purposes from time to time, especially in the pubertal period, is quite limited. Therefore, the current study aimed to determine the cardiac hypertrophy potential of EPO by making morphometric measurements in the hearts of pubertal rats.
The use of erythropoietin as a performance-enhancing drug in sports is based on its ability to increase oxygen capacity through erythropoietic stimulation. Sufficient oxygen delivery to the heart and muscles is crucial, particularly in endurance sports like swimming and athletics. Artificially increasing the oxygen intake capacity of athletes is often done to improve their performance. However, this approach can be risky as it ignores the potential side effects. Erythropoietin (EPO) is a substance that can increase hematocrit levels, leading to erythrocytosis, heart failure, myocardial infarction, seizures, peripheral thromboembolism, pulmonary embolism, and sudden deaths [25]. It has been reported that fluid losses during physical exercise may contribute to the development of the above risk factors by causing an increase in blood viscosity [26, 27]. A study was conducted to investigate the cardiovascular effects of erythropoietin in rats subjected to a chronic/regular physical exercise model [25]. The study found that the use of recombinant human erythropoietin (rhEPO) not only promoted hyperviscosity but also caused other harmful cardiovascular and thromboembolic changes, including hypertension, cardiac hypertrophy, sympathetic and serotonergic overactivity. The study concluded that rhEPO has serious negative effects on the cardiovascular system. In the current study, the application of EPO did not result in a statistically significant difference in LVPT, LVM, and LVMI, which are important measurements for left ventricular hypertrophy, in both genders, regardless of physical activity. It has been reported that regular exercise concurrent with EPO use may increase the risk of cardiovascular mortality due to left ventricular hypertrophy, characterized by increased left ventricular wall thickness [25, 28]. The discrepancy between these data and the current study findings can be attributed to differences in the type of EPO used and the duration of exercise. Piloto et al. (2009) administered rhEPO in conjunction with chronic exercise three times a week for eight weeks, with each session lasting one hour. In contrast, the current study administered Erythropoietin alfa along with exercise four times a week for four weeks, with each session lasting half an hour. The current study concluded that the use of EPO in combination with shorter-term/non-chronic exercise has a limited potential to cause left heart hypertrophy. However, the fact that some deaths allegedly caused by EPO derivatives occurred not during exercise but during periods of physical inactivity shows that their harmful effects may also occur in the future. Therefore, further studies considering the half-life of EPO in the blood and following up subjects after stopping short-term exercise would be beneficial, even though no sudden deaths occurred in the current study.
In the present study, an increase in IVST, RVT, and mild CCD values was detected in the FS group. It was thought that this condition, which was mostly due to right heart hypertrophy, might have occurred because of exercise-induced pulmonary hypertension. In the FSD group, unlike the FS group, a decrease in IVST, RVT, CCD, and CSA values was noted. This situation was attributed to the acute dilatation that occurred as a result of the expansion of the diameters of the ventricular lumens as a result of filling with blood, parallel to the increase in the hematocrit level due to the use of EPO. Similarly, a decrease in IVST, RVT, and CSA and an increase in LVDL and CCD were observed in the FD group. Upon evaluation, it was concluded that EPO use in females could cause acute cardiac dilatation, characterised by thinning, especially in the right heart wall and interventricular septum, due to intraventricular hemoconcentration.
The increase in LVLD in the MS group was not found to be significant, partly because its decrease in the EPO groups was not supported by other measured parameters. In the MSD group, a decrease was noted in both the BSA and BW groups. Caillaud, Connes [29] reported that EPO increased body lipid oxidation during exercise in humans. In this respect, it was thought that this situation observed in the MSD group might be due to the decrease in body fat mass.
The cardiac cytoprotective effects of EPOs, which are extensively used as anti-anemics especially in chronic renal failure, for acute conditions such as heart failure, myocardial infarction and cardiac arrest, apart from erythropoiesis, have not yet been confirmed by clinical studies [30, 31]. In fact, scientific data showing that EPO increases the performance of athletes is also still insufficient [30]. It is important to consider that the perceived advantages of EPO application may pose a life-threatening risk when compared to the complications of tissue hypoxia in vital organs. This can occur due to increased hematocrit, blood viscosity, peripheral flow resistance, and possibly arterial hypertension and microcirculation disorders. As a matter of fact, in the current study, although left heart hypertrophy was not detected morphologically with short-term exercise and EPO application, findings that could affect cardiac functions in the future and even progress to hypertrophic cardiomyopathy were observed. Therefore, it was concluded that irrational and uncontrolled EPO use has the potential to lead to serious cardiovascular disorders and that this effect may be more pronounced with prolonged / chronic exercise and long-term use.