Erythropoietin Treatment Improves Peak VO 2 and Oxygen Uptake Efficiency Slope without Changing VE vs . VCO 2 Slope in Anemic Patients

C l i n M e d International Library Citation: Goda A, Itoh H, Ebi Y, Kondo K, Maeda T, et al. (2015) Erythropoietin Treatment Improves Peak VO2 and Oxygen Uptake Efficiency Slope without Changing VE vs. VCO2 Slope in Anemic Patients. Int J Clin Cardiol 2:023 Received: February 16, 2015: Accepted: March 17, 2015: Published: March 20, 2015 Copyright: © 2015 Goda A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Goda et al. Int J Clin Cardiol 2015, 2:2 ISSN: 2378-2951


Introduction
Exercise tolerance in anemic patients is markedly reduced, and shortness of breath is a common symptom in these patients.The mechanism of shortness of breath is thought that reduction of hemoglobin concentration may result in exercise intolerance by decreasing oxygen (O 2 ) delivery.It has been reported that erythropoietin (EPO) treatment for anemia improves exercise tolerance (i.e.peak oxygen uptake (peak VO 2 )) [1][2][3][4][5][6].In chronic renal failure (CRF) patients with anemia and reduced cardiac function, treatment of the anemia with EPO has improved many of abnormalities seen in chronic heart failure (CHF), reducing left ventricular hypertrophy, preventing left ventricular dilatation, and increasing the left ventricular ejection fraction (LVEF) [7][8][9][10].
dysfunction, ischemic heart disease who stopped exercise testing due to chest pain or significant ST depression in exercise electrocardiogram (ECG), or a history of EPO treatment within the past 6 months.The underlying renal diseases included chronic glomerulonephritis in 26 patients, diabetic nephropathy in 6 patients, and other chronic renal disease in 5 patients.All the patients were on the 4 hours, 3 times a week regular hemodialysis.The averaged hemodialysis period was 6.6 ± 5.2 years.
This study was approved by the committee on clinical study and ethics.The purposes and risks of the study were explained to the patients, and informed consent was obtained from each patient.

Study protocol
EPO (1500 or 3000 unit) was administrated intravenously 3 times per week, after each dialysis session.For the patients whose serum ferritin was less than 1000ng/ml, oral or intravenous iron was supplied.Hemoglobin and hematocrit were measured before dialysis once a week.The patients were evaluated measurement before treatment and after the hematocrit reached the target range of 30% to 35%.Serum EPO was measured before and after treatment.

Echocardiography
M-mode and 2-dimensional echocardiographic studies were performed before and after EPO treatment in all patients.We used an ultrasound system with a 2-dimensional mechanical sector scanner (SSD-2000; Aloka; Tokyo, Japan).Left ventricular end-diastolic dimension (LVDd) and end-systolic dimension (LVDs) were obtained from the apical 4-and 2-chamber views from which LVEF was automatically calculated by a modified Simpson's method [16].

Blood gas analysis and memodynamic measurements
Arterial blood gases were measured before and after EPO treatment in all patients at rest before hemodialysis.The partial pressure of arterial O 2 (PaO 2 ), arterial CO 2 (PaCO 2 ), and the pH were measured with a blood gas analyzer (ABL 300, Radiometer, Copenhagen, Denmark).Cardiac output was measured by the dye dilution method using an earpiece with a dye densitometer (MCL-4200, Nihon Coden, Tokyo, Japan) [17].A 19G cannula was placed in the artecubital vein, and 5 mg of indocyanine green dissolved in 5 ml distilled water was injected through this cannula at rest.O 2 delivery was calculated using the formula as follows; hemoglobin X 1.36 X O 2 saturation in arterial blood X cardiac output.

Cardiopulmonary exercise test
Cardiopulmonary exercise test was performed before and after EPO treatment on the next day to the first hemodialysis of the week.An incremental symptom-limited exercise test using to ramp protocol was performed with a treadmill.After 4-min standing on the treadmill, exercise began with a 4-min warm-up at the speed of 1.0km/h, followed by an increase in grade and speed according to treadmill-ramp protocol.Treadmill-ramp protocol was developed in Japan which was designed to increase VO 2 linearly at the rate of 3/ min/kg based on the formula as follows; VO 2 =0.15S*2 + 0.14 SG + 0.45 S + 0.4 G + 0.423, where S is speed (km/hr) and G is grade (%) [18].Heart rate and ECG were monitored continuously during the test with a Stress System ML-5000 (Fukuda Denshi Co. Ltd.; Tokyo, Japan).Cuff blood pressure was measured at rest, and every minute during the test.

Respiratory gas analysis
VO 2 , VCO 2 , VE, respiratory rate (R-R), and tidal-volume (TV) were measured throughout the test using an Aeromonitor AE-280S (Minato Medical Science; Osaka, Japan).Prior to calculating the parameters from respiratory gas analysis, an eight-point moving average of the breath-by-breath data was obtained.Peak VO 2 was defined as the average value obtained during the last 30 seconds.The anaerobic threshold (AT) was determined by the V-slope method [19].VE vs. VCO 2 slope was calculated from the start of incremental exercise to the respiratory compensation point by least squares linear regression, as previously described [20].The oxygen uptake efficiency slope (OUES) describes as the gradient of the linear relationship between VO 2 and VE during incremental exercise via a singlesegment logarithmic expression of VE and is defined as the regression slope "a" in VO 2 = a log10 VE + b [13].

Statistics
Clinical and exercise variables for before and after treatment were compared through the use of and paired t tests.Statistical comparisons were considered significant for probability value <0.05.

Laboratory data
All thirty-seven patients responded to the treatment with EPO without apparent side effect.Duration of therapy averaged 160 ± 49 days (between 86 and 275 days).Mean values of hemoglobin and hematocrit increased significantly during the study period from 6.4 ± 0.9 to 10.8 ± 1.0g/dl (p<0.001) and from 19.0 ± 2.5 to 32.9 ± 3.1 % (p<0.001),respectively (Table 1).Serum EPO did not change significantly by during the treatment (from 17.3 ± 4.5 to 19.3 ± 5.7mIU/ml, p=0.128).Among 37 patients, 31 patients prescribed elemental oral or intravenous iron.

Blood gas analysis and hemodynamic measurements
PaCO 2 at rest increased significantly from 35.7 ± 3.7 to 37.5 ± 3.6 Torr (p=0.046).PO 2 unchanged from 90.9 ± 14.8 to 90.9 ± 12.7 Torr (p=0.979), and pH unchanged from 7.353 ± 0.036 to 7.339 ± 0.039 (p=0.125).Before treatment, resting cardiac output was 8.0 ± 1.6l/min, which is high output state caused by anemia.It significantly decreased to 5.6 ± 1.2l/min (p<0.001) in accordance with the increase in hemoglobin, but it still is upper limit of normal range.O 2 delivery at rest increased from 663.8 ± 161.1 to 793.4 ± 188.5ml/min (p=0.004).O 2 delivery increased significantly with improving anemia, even though cardiac output at rest decreased.

Exercise testing
Exercise measurements are shown in Table 2. Heart rate and systolic blood pressure at both of rest and peak exercise did not change by the treatment.However, at given exercise time, heart rate and systolic blood pressure decreased after the treatment, and heart rate at AT decreased significantly from 113.4 ± 23.9 to 102.5 ±19.0bpm (p=0.034).Exercise time and time at AT after starting ramp exercise also prolonged significantly from 393.1 ± 66.0 sec to 449.4 ± 86.8 sec (p<0.05) and from 467.8 ± 154.4 sec to 584.5 ± 145.6 sec (p<0.001).Peak VO 2 increased significantly from 15.7 ± 5.3 to 18.8 ± 5.3ml/min/kg (p=0.017)(Figure 1), which represented a mean increase of 20% over the baseline measurements.There was weak correlations between change in Hb and change in peak VO 2 (r=0.330,p=0.046).AT VO 2 and ΔVO 2 /time did not change between before and after treatment.

Discussion
In the present study, treatment for anemia resulted in 1) increasing O 2 delivery at rest, Peak VO 2 , and OUES, 2) decreasing cardiac output at rest, VE, and VE vs. VO 2 relationship, and an 3) unchanging VE vs. VCO 2 relationship.The result of the present study has revealed that anemia affected VE vs. VO 2 but not VE vs. VCO 2 relationship in CRF patients.

Anemia and exercise tolerance
The treatment of anemia with EPO improves exercise tolerance, which has previously been described in many studies [1][2][3][4][5][6].In our present study, peak VO 2 represented a mean increase of 20% over the baseline measurements in agreement with the other reports.The mechanism by which EPO improves exercise tolerance has been presumed to be increased hemoglobin concentration leading to increased O 2 delivery.In CRF patients, EPO has been shown to improve skeletal muscle function and O 2 use, as well as endothelial function [21].In our present study, instead of skeletal muscle function and O 2 use, cardiac output was actually measured by the dye dilution method, and O 2 delivery was calculated.We demonstrated that O 2 delivery increased along with the improvement of anemia.

OUES
A non-linear measure of the ventilatory response to exercise (i.e.OUES) has been described, initially in young patients with cardiac disease [13].The OUES is derived from the single-segment logarithmic relation between VO 2 and VE during incremental exercise.OUES incorporates in a single index not only cardiovascular and peripheral factors that determine VO 2 but also pulmonary factors that influence the ventilatory response to exercise.It has been showed that OUES is significantly correlated to peak VO 2 in patients with CHF [22] and is not influenced by the duration of the exercise test, or by achieved exercise intensity.However, the effect of anemia on OUES hasn't been well known.In our present study, OUES improved along with improvement of anemia.Its mechanism might be similar in peak VO 2 , due to increasing O 2 delivery and VO 2 and decreasing VE.Anemia and VE vs. VCO 2 relationship VE vs. VCO 2 slope, which reflects a ventilatory efficiency during exercise, has been emphasized a powerful predictors of prognosis and severity of CHF [11,12].Ventilatory efficiency depends on pulmonary hemodynamics and related parameters such as ventilationperfusion mismatch, skeletal muscle ergoreceptor and peripheral chemoreceptor sensitivity, and heightened sympathetic activity.Until now, the effects of EPO on VE, VO 2 , and VCO 2 kinetics and VE vs. VCO 2 slope are not well recognized in anemic patients.
On the patients of iron deficiency anemia, Davies et al. [23] revealed that improvement of anemia decreased VE at the same exercise stage.Robertson et al. [1] reported that correction of anemia significant by decreased VE in CRF patients.But they did not mention about the physiologic mechanism of this changing.On the patients of HbSC sickle cell patients, Oyono-Enguelle et al. [24] reported VE in anemic patients (HbSC patients) drifted upward than that in normal patients (HbAA patients).They expected that caused by changes of the body temperature, epinephrine and norepinephrine, acidosis, and lactate metabolism.
Similarly, in our present study, VE decreased by improving anemia.Treatment for anemia might improve tissue O 2 supply and muscle function in terms of lactate production and/or utilization, then improvement of acidosis in the tissue during exercise lead the decreasing the VE in the given exercise intensity.That would be  explained by the delay of AT appearance after treatment and decrease of heart rate at AT. VE is mainly determined by the rate of CO 2 production, the physiologic and anatomic dead space, and the level at which PaCO 2 during exercise.VE vs. VCO 2 slope was steeper in CHF patients than normal subjects, because it is considered to be derived from the ventilation-perfusion mismatch and the increased ratio of physiologic dead space to TV, which was due mainly to the inappropriate increase in cardiac output during exercise [25].However, in case of anemia without CHF, VE vs. VCO 2 relationship are parallel, because dead space ventilation doesn't increase.

Ventilatory efficacy for VO 2 and VCO 2
Improvement of anemia decreases VE at the same exercise stage, which results in improvement in OUES.In contrast, the kinetics of VE and VCO 2 are parallel, which results in unchanging VE vs. VCO 2 slope.In the point of O 2 transport capacity during exercise, anemic state is similar with the state of decreased pulmonary blood flow with normal hemoglobin concentration.In contrast, in the point of the CO 2 kinetics, differ from O 2 kinetics, CO 2 is transported across alveolar membrane by diffusion mechanism, which means CO 2 excretion is not disturbed when pulmonary blood flow is maintained even in anemic state.In summary, hemoglobin affects O 2 but not CO 2 transport.The improvement of CHF results in the improvement of both VE vs. VCO 2 slope and OUES, however, the improvement of anemia results in unchanging of the VE vs. VCO 2 slope and changing of the OUES.That is the difference between ventilatory efficacy for VO 2 and VCO 2 in the treatment of anemia.

Limitation
In the interpretation of our study results, some limitations should be considered.The major limitations of this study were the small number of patients and the lack of a control group.In case of CRF patients, improvement of anemia induces improvement of hyperdynamic state.However, the physiological mechanism at the pulmonary alveolar membrane level is similar with CHF patients, so it was worth in considering about VE, VO 2 and VCO 2 kinetics in anemia in this model.

Conclusions
The treatment of anemia improved peak VO 2 and OUES without affecting VE vs. VCO 2 slope significantly.In evaluating the efficacy of treatment for CRF patients with anemia the VE vs. VO 2 relation rather than the VE vs. VCO 2 should be used.

Figure 1 :
Figure 1: Changes in Oxygen Uptake and Minute Ventilation during Exercise

Table 1 :
Laboratory data, echocardiography, blood gas analysis and hemodynamic measurements between Pre and Post EPO treatment

Table 2 :
Cardiopulmonary exercise testing parameters at rest and exercise between Pre and Post EPO treatment