The present study analysed heart function and mechanics during moderate altitude exposure in subjects administered with rHuEPO or isotonic saline. Here, we show that rHuEPO injections during an altitude training camp do not importantly alter heart function. We observed a blunted untwisting velocity induced by rHuEPO which may suggest an impaired LV relaxation during diastole. However, this effect could also reflect that subjects receiving rHuEPO do not need to activate a compensatory mechanism such us untwisting in order to maintain a given CO.
4.1. Methodological considerations
Several important methodological considerations should be taken into account when interpreting our data. Indeed, preliminary data was collected during acclimatisation (i.e. 3 days after arrival to 2230m), immediately before rHuEPO and placebo injections. This is of importance as most of the acute effects of hypoxia on the heart are evident within the first 4 days following exposure [17]. For instance, early (E wave) and late (A wave) left ventricular filling are not altered after 2 days of HA exposure [26] while a reduced early ventricular filling is evident after 2-6 days in hypoxia [17]. In the present study, we observed an increment of the E/A ratio by means of reduced late filling. While this seems to be inconsistent with the literature [20, 21, 25, 27], this is probably a result of a long-term normalization following altitude acclimatization. In agreement, a rapid increase in late filling has been reported upon arrival to 4320m above sea level [17]. In this regard, it must be highlighted that the present study design does not allow to reach conclusions on the effects of mild hypoxic exposure on heart function but may provide indications of longer term adaptation to mild hypoxia.
In addition, PAAT, an accurate marker of pulmonary arterial systolic pressure [28], was unaltered under our experimental conditions. Thus, although inferred from an indirect measurement, pulmonary arterial systolic pressure appears unaltered by moderate altitude as well as by rHuEPO.
4.2. Left ventricle filling and mechanics in response to rHuEPO
The store and release of energy through elastic components is a key process linking systole and diastole. The diastole phase consists of two phases: initially, due to the stored energy of the elastic component, the pressure gradient between the atria and the ventricles is high and ventricular filling is rapid (the phase of rapid early filling). Under normal circumstances about 70% of ventricular filling occurs during this phase. As diastole progresses, ventricular pressure rises and the rate of filling slows (i.e. diastasis phase). The final ~25% of filling during ventricular diastole results from atrial contraction (i.e. atrial systole phase) [29].
Untwisting occurs during the diastole phase of rapid early filling and is directly influenced by the relaxation of cardio myocytes and the release of potential energy stored during systole [30]. Interestingly, we found that untwisting velocity decreased in the rHuEPO group following 3 weeks of altitude exposure. Moreover, while placebo group increased %UTIVRT by ~20%, the rHuEPO group showed a ~13% decrement. There are two potential reasons for these observations. In one hand, rHuEPO may alter early diastolic filling during HA exposure; however, E´mean was not altered by rHuEPO thus excluding a potential alteration in myocardial relaxation. Moreover, we found no effect of rHuEPO in early diastolic filling (E wave) or filling pressures. Therefore, it seems unlikely that rHuEPO alterations of myocardial mechanics results in altered early LV filling. However, further studies perhaps examining subendocardial and subpericardial are needed in order to elucidate whether rHuEPO could differently affect either layer during altitude exposure.
On the other hand, rHuEPO is better known for its effect outside the cardiovarcular system in humans. For instance, increased red cell production, angiogenesis, myogenesis, shift in muscle fibre types, and oxidative enzyme activities in skeletal muscle has been reported [31] that may also lead to improve maximal oxygen uptake [32]. In this scenario, rHuEPO may help to maintain a given CO through haematological and metabolic mechanisms without an increased untwisting rate. In agreement with this hypothesis, subjects in the rHuEPO group showed higher erythropoietic response than subjects in placebo group [6]. Therefore, while the rHuEPO dose used in the present study is of physiological relevance [32], it seems unlikely to alter cardiomyocyte function.
Finally, it has been reported that untwist velocity increases immediately in response to altitude exposure, an effect that is maintained for 4 days, but which is normalized to sea levels after 6 days [17]. Thus, the lack of effect of altitude on this heart mechanics parameter could be easily explained by the fact that our preliminar measurements were obtained 3 days after arrival to altitude. In contrast, we were able to detect the common observation of increased twist angle in response to altitude exposure [17, 21, 25, 29]. In this regard, it is important to highlight that endurance training decreases twist angle without altering untwist velocity [34]. Thus, as our sample was already trained subjects then, an increased twist angle would be easier to detect even with the design limitations discussed above.