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European Journal of Heart Failure 2006 8(5):443-450; doi:10.1016/j.ejheart.2005.10.017
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© 2005 European Society of Cardiology

Percutaneous endocardial injection of erythropoietin: Assessment of cardioprotection by electromechanical mapping

Korff T. Krausea,*,1, Kai Jaqueta,1, Stephan Geidelb, Carsten Schneidera, Christina Mandelc, Hans-Peter Stolld, Klaus Herttinga, Tobias Harlea and Karl-Heinz Kucka

a Cardiology, St. Georg Hospital Hamburg, Germany
b Cardiac Surgery, St. Georg Hospital Hamburg, Germany
c Institute of Experimental Oncology and Therapy Research, Technical University of Munich Munich, Germany
d Cordis European Head Quarter Waterloo, Belgium

* Corresponding author. AK St. Georg, Herzkatheterlabor, Lohmühlenstr. 5, 20099 Hamburg, Germany. Tel.: +49 40 2890 2033; fax: +49 40 2890 4444. Email address: korff.krause{at}web.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Apart from its well-known stimulation of erythropoiesis, erythropoietin (EPO) exhibits angiogenic and anti-apoptotic effects. These cellular protective effects have also been described in experimental acute myocardial infarction models. We investigated the effects of EPO in a porcine model of chronic progressive myocardial ischaemia.

Methods: At weeks 2 and 6 after implantation of a circumflex ameroid constrictor, endocardial electromechanical NOGATM system (Biosense Webster, Inc., California, USA) mapping of the left ventricle, coronary and ventricular angiography, as well as echocardiography were performed. Two weeks after ameroid placement, 13 pigs were randomized with 7 pigs receiving 10.000 U EPO and 6 pigs receiving placebo into the ischaemic region using a NOGATM guided percutaneous transendocardial injection catheter, MYOSTARTM. After 6 weeks, histology (Masson's Trichrome) was analyzed.

Results: Endocardial electromechanical mapping showed an increase of mean unipolar voltage (UV) amplitude in the ischaemic myocardial segments in the EPO-treated animals (8.5 mV pre and 10.6 mV post treatment) and a significantly reduced ischaemic surface area compared to the control group (19% vs. 41%) suggesting a decline in ischaemic injury. Echocardiography revealed 2,2 hypokinetic segments of the lateral wall in the EPO group vs. 3,3 in the control groups. The mean ejection fraction was 64% in the EPO group and 55% in the placebo group. Quantitative histological analysis of the ischaemic regions revealed a reduction of myocardial fibrosis (8% vs. 28%) in the EPO group.

Conclusion: Endocardial EPO injection may induce cardioprotective effects in hibernating myocardium and may attenuate the progression of ischaemic tissue damage.

Key Words: Percutaneous endocardial injection • Cardioprotection • Electromechanical mapping

Received April 10, 2005; Revised August 4, 2005; Accepted October 20, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Erythropoietin (EPO) is a cytokine known to promote erythropoiesis. The therapeutic application of recombinant erythropoietin (rhEPO) for patients with renal anaemia was introduced in the mid-1980s. Recently, neuroprotective effects of EPO have been shown in preclinical stroke models [1]. Based on anti-apoptotic effects, a significant reduction of cerebral ischaemic injury was documented in a rat model of cerebral ischaemia. A first clinical safety and proof-of-principle study revealed a positive effect in patients with acute cerebral ischaemia [2]. Based on these effects, EPO has been most recently investigated in experimental acute myocardial infarction models. In these preclinical studies, the EPO receptor (EPOR) was identified in myocardial muscle and fibrotic cells [3,4]. Also, differentiation of myoblasts induced by EPO and EPOR activation has been shown [5]. The anti-apoptotic pathway of EPO involves protein kinase cascades including Janus-associated kinase-2 (Jak2), phosphatidylinositol 3-kinase (PI3K)/Akt and Ras-MAP kinase [6], and activation of the Act kinase pathway [7]. These enzyme pathways are also involved in preconditioning cardioprotection in ischaemic/reperfusion injury [8].

Besides these effects, other direct actions of EPO were described such as mobilization of endothelial progenitor cells [9], angiogenic activity in myocardial endothelial cells [10], and decreasing myocardial apoptosis following myocardial infarction [11]. Also, hypoxia-induced cellular apoptosis was attenuated with EPO in a cardiomyoblast cell line [11]. In vivo studies showed that EPO can reduce infarct size and significantly enhance cardiac function and contractility following myocardial ischaemia in a coronary vessel ligation model [12].

Those studies suggest an anti-apoptotic effect of EPO despite the fact that in acute myocardial infarction, necrotic cell death is evident. Based on investigations of acute myocardial infarction, the apoptotic pathway of cell death seems to be predominant in the first hours of ischaemia whereas in later stages necrotic myocytes are more evident [13]. We used the ameroid constrictor model to induce a chronic ischaemia resulting in hibernating myocardium because myocardial cell apoptosis was also found to be responsible for wall motion disturbances [14] and therefore a cardioprotective effect of EPO can be assumed. We investigated for the first time whether cardioprotection induced by EPO is also detectable in chronic ischaemia. Therefore, we assessed electromechanical mapping in vivo and echocardiographic follow up as well as histological analysis.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Animal model
Seventeen domestic pigs were housed and studied according to the guidelines and approval of the local bioethical committee in Kiel, Germany. The investigation conforms to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996). Four pigs died before evaluation due to infectious diseases (pneumonia, septicaemia) and were excluded from the study. No death was catheter-related.

All pigs were 3-4 months old when the ameroid constrictor was placed around the circumflex artery during off-pump thoracic surgery under anaesthesia and mechanical ventilation. All pigs had a weight of 28-34 kg. After 2 and 6 weeks, coronary angiography, electroanatomical mapping, and echocardiography were performed under propofenol anaesthesia. The animals in the study were randomized and the investigators were blinded. Seven pigs received 10.000 U EPO via endocardial injection and 6 pigs received placebo injections at week 2 directly after the first mapping procedure. After 6 weeks, all animals were sacrificed and the hearts excised.

2.2. Electromechanical mapping and endocardial injection
After biplane coronary and left ventricular angiography, a mapping catheter was placed via the aortic valve into the left ventricle. The endocardial mapping technology using the NOGATM system has been described elsewhere [15,16]. The initial endocardial points were acquired at the apical, septal, and lateral walls under fluoroscopic and echocardiographic guidance. Subsequently, 68±20 points were acquired with a minimum of 3 points in each of the 12 segments of the heart. All points had to meet the recommended stability criteria (cycle length <10%; loop stability <6 mm; location stability <4 mm). Those points that were unrelated to the left ventricle (e.g., left atrium and aorta) and points not representing the inner surface of the LV were eliminated online during the procedure.

At week 2, after completing the left ventricular mapping procedure, all pigs received endocardial injections using the MyoStarTM injection catheter. The area at risk was defined according to the unipolar voltage (UV) values. Fig. 2 shows computerized mapping of the ischaemic zone in the area at risk (red zone). In the area at risk, 10 injections of 100 µl volume each were performed (Fig. 2). At week 6, right after the second mapping procedure, the area at risk was marked with ink using the echo-guided and NOGATM-guided injection catheter MYOSTARTM so that the tissue specimen could be identified precisely after sacrifice of the animals.

2.3. Assessment of unipolar voltage (UV)
Visual inspection of the colour-coded maps was used to identify low voltage regions. For a segmental analysis, the NOGATM endocardial surface was divided into nine segments. The data are presented in a bull's-eye projection. The LV was divided into three areas: apex (20%), mid-ventricle (40%) and base (40%). The base and mid-ventricle were further segmented into anterior (80°), septal (120°), inferior/posterior (80°) and lateral (80°). All segments defined online were compared at week 2 and week 6. According to Botker et al. [17,18] ischaemic segments were identified by the discriminative value of 68% of the normal segments. This approach has a better sensitivity and a specificity of 78% for the detection of dysfunctional myocardium. Nominal cut-off levels were shown to be less specific (specificity 68%). Those segments with a mean value <68% UV amplitude were counted at week 2 and week 6. The mapping procedure can generate values with some between-individual and within-individual variability. By using normalized values [17], we were able to compare the mapping values in follow-up investigations for each animal in this study. In this fashion individual values could be obtained before and after treatment and expressed in relation to each other.

Based on standard reference frame, the two-dimensional surface areas and the visualized extension of the ischaemic areas were quantified. Those areas exhibiting a UV <68% of normal UV values were set to outline abnormal myocardium by computer-generated colour imaging (red). Normal UV values were obtained by calculating the mean of all UV values excluding the mitral valve annuli, which were outlined before.

The endocardial surface area was divided into multiple, non-overlapping triangular segments. The extent of the low voltage area representing the sum of these contiguous segments was obtained by using an area calculation. By using the same algorithm, the entire LV endocardial surface was divided into non-overlapping segments. The sum of all represented the total left ventricular inner surface [19]. The area at risk was measured in percentage of the total inner surface area.

2.4. Mechanical data
By calculating the local linear shortening (LLS), the regional contractility was assessed. This algorithm calculates the fractional shortening of the regional endocardial surface at the end of systole as described previously [15,16].

2.5. Material
Erythropoietin (Jansen-Cilag, Germany; OrthoBiotech, NJ, USA); placebo solution: NaCl 74.90 mM, NaH2PO4 8 mM, Na2PO4 11.27 mM, Glycine 66.67 mM, Tween 80 0.03%.

2.6. Echocardiography
Two experienced cardiologists, who were blinded to the injection group, assessed regional contractility by using standard views according to the guidelines of the American Society of Echocardiography. The parasternal short and long axis view, as well as the apical 4- and 2-chamber views were performed. In a 16-segment model, the regional contractility was determined using a semiquantitative scoring system (1=normal; 2=hypokinetic; 3=akinetic; 4=dyskinetic). LV volumes and ejection fraction (EF) were measured by the biplanar Simpson's method in the 2- and 4-chamber view in the end of diastole and the end of systole. All measurements were averaged on three cardiac cycles. The echocardiographic investigations were performed at week 2 (time of injection) and week 6 after ameroid constrictor implantation. 2D images were obtained using an ultrasound system with a 5-MHz linear transducer (Vivid 5, General Electric, USA).

2.7. Histology
The hearts were excised and fixated with 10% phosphate-buffered formalin. Heart tissue from the ink-marked area at risk and the remote septal area were embedded in paraffin, sectioned (7 µm) and stained with Elastica-van-Giesson, Masson's Trichrome, and Hematoxylin/Eosin. Light microscopy was performed with an IX 71 Olympus microscope (Olympus, Hamburg, Germany).

Morphometric quantification of fibrosis was performed with the Analysis digital soft imaging system (version 3.2) according to the software instruction manual (SIS, Munster, Germany). Fibrosis was analyzed in five bi-colour-coded views in each sample of the Masson's Trichrome stained specimen. Using planimetry, the degree of fibrosis was expressed as percentage of myocardial tissue per field of view (2.38 mm2 each) by Masson's Trichrome and Elastica-van-Giesson staining.

2.8. Statistical analysis
Values are expressed as mean standard deviation. The UV and LLS values as well as the extent of fibrosis in the EPO group and the control group were compared using the ANOVA analysis and the two-sided Mann-Whitney test. Statistical significance was accepted for a p-value <0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Electromechanical mapping
3.1.1. Local electrical function
Mean unipolar voltage (UV) amplitude of the area at risk decreased to 8.87 mV in the control group and 8.84 mV in the EPO group at week 2 after ameroid placement, so that both groups had significantly decreased UV in the area at risk compared to remote myocardial segments (p<0.05). At week 6, in the area at risk the mean UV in the EPO-treated animals increased to 10.57 mV and in the control group it decreased to 8.30 mV (but did not reach statistical significance), p=0.053 (Fig. 1). Based on individual cut-off values calculated as a percentage of UV in normal segments (normalized UV values), the increase of the UV in the area at risk was also not significant.


Figure 1
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  		Fig. 1 After EPO injection at week 2 the mean UV of the area at risk was increased at week 6 compared to the area at risk of the control group, but not significantly (p>0.05).

 
Based on the optimal discriminatory value between normal and myocardial dysfunction, the mean count of ischaemic segments (analyzed with the bull's eye segment model) in the EPO group decreased from 3.6 before to 2.7 after treatment. In the control group, the segment number increased (mean 2.8 and 5.5 segments, respectively), which was significant, p=0.002. Representative pre- and post-treatment maps of pigs that received EPO or control are shown in Fig. 2.


Figure 2
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  		Fig. 2 NOGA inner surface maps of the left ventricle (LV) based on the unipolar voltage (UV). (A) and (C) represent LV maps pre-EPO injection at week 2. (B) and (D) show maps after EPO injection at week 6. The red zone represents the area at risk. (E) and (G) are pre-injection maps and (F) and (H) are post injection maps of control group animals with augmentation of the red zone. Pink and brown spots are marked injection points.

 
The defined colour-coded ischaemic areas were expressed as percent of total inner surface area at week 2 and week 6 after ameroid placement. In the EPO group, this area was 21.4 (±7.8)% before injection and 19.4 (±10.2)% after 6 weeks. In the control group, the area expanded from 26.3 (±9.8)% to 41.0 (±5.5)% of the inner surface (p=0.0007) as shown in Fig. 3.


Figure 3
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  		Fig. 3 Mean extension of the area at risk expressed as percentage of total inner surface area according to the NOGA maps based on the UV values. The control group showed a progressive extension of the ischaemic area from week 2 to week 6 (p=0.0007) in contrast to the EPO group.

 
3.2. Local linear shortening
We found no significant difference in the analysis of local linear shortening (LLS) between the EPO and the control group. In both groups the LLS in the area at risk decreased: –5.09% in the EPO group (17.51% to 12.42%) and –3.95% (16.98% to 13.03%) in the control group (p>0.5).

3.3. Echocardiography
The mean EF remained nearly unchanged in the EPO group pre and post treatment (64% vs. 66%) whereas it was reduced in the control group (60% vs. 55%), p>0.05 (Fig. 4).


Figure 4
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  		Fig. 4 Comparison of ejection fractions (EF) in the EPO group and the control group. The control group had a mild reduction in the EF (not significant).

 
Based on a 16-segment analysis hypokinetic segments were identified in the posterolateral mid and basal, inferior mid and basal and apical lateral region. The EPO group showed 2,8 hypokinetic segments before and 2,2 hypokinetic segments after treatment whereas the control group had 2,5 pathological segments before and 3,3 hypokinetic segments after endocardial injection.

3.4. Coronary angiography
Standard biplane coronary angiography at week 2 and week 6 revealed total occlusion of the proximal circumflex artery in all animals. No collateralization could be documented by angiographical visualization of right and left coronary artery.

3.5. Histology
The area at risk was identified by endocardial ink injections in the final experiments using the NOGATM guidance. The morphometric assessment revealed that the degree of fibrosis was significantly lower in the EPO group compared to the control group: 8% vs. 27% as shown in Fig. 5 (p=0.01). Also, we observed that the area of patchy and interstitial fibrosis extended through more than half of the myocardial depth in 4 of 6 pigs in the control group and in 1 of 7 pigs in the EPO group (67% vs. 14%). Representative histological specimens are shown in Fig. 6.


Figure 5
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  		Fig. 5 Mean connective tissue content (percentage of cross-sectional area) in the area at risk was significantly reduced in the EPO-treated animals (p=0.01).

 


Figure 6
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  		Fig. 6 (A) and (C) Normal myocardium (Masson's trichrome staining), and (B) representative section of the area at risk in the EPO group. (D) is an example of the control group with a high degree of fibrosis.

 
3.6. Laboratory results
Haemoglobin (Hb) appeared to increase over time in both the EPO and the control groups: 8.9±0.9 g/dl pre treatment and 9.7±1.1 g/dl post treatment vs. 7.9±0.8 g/dl and 9.2±0.9 g/dl, although the differences were not statistically significant. These values are in the normal range of growing pigs.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
We investigated for the first time the effect of EPO in a porcine chronic myocardial ischaemic model. Our results indicate that EPO has cardioprotective effects on hibernating myocardium. In a randomized blinded study, we demonstrated a decrease of interstitial fibrosis and protection against progressive expansion of the ischaemic area in hibernating myocardium in a porcine ameroid constrictor model. These findings are in accordance with recent studies on cardioprotective effects of EPO administration in rat acute infarction models.

In contrast to all studies so far which investigated the effect of systemically applied EPO in acute infarction, in our model, hibernating myocardium is exposed to EPO via direct intramyocardial injection. Intramyocardial injection was preferred, because systemic application of EPO potentially increases the haematocrit and precise injection into the area at risk implies higher localized intramyocardial concentration of EPO.

There are major differences between rodents and large mammals in mechanisms of myocardial contraction and ischaemia, as well as a lack of pre-existing collaterals in the swine heart, thus the cardiac physiology of swine is very similar to humans, making our model closer to clinically relevant conditions than the aforementioned rodent models [20].

In addition to echocardiography, we used the computerized electromechanical mapping system NOGATM to evaluate electrical activity (endocardial voltage) and regional wall motion (local length shortening). We found a decrease in UV in the area at risk in both the EPO and control group to 8.48 and 8.87 mV. After endocardial EPO administration the UV increased to 10.57 mV in the ischaemic segments. In the control group it decreased to 8.3 mV, although, this did not reach statistical significance. During the follow up, the segment number and endocardial surface area of ischaemic myocardium increased in the control group indicating an active process of chronic ischaemia and hibernation [21] induced by chronic progressive stenosis and finally CX-occlusion caused by the ameroid constrictor 2 weeks after implantation. In the EPO group, the segment number and surface area were significantly lower compared to the control group implying a limitation in size of the ischaemic area.

The amount of fibrosis correlates with mechanical recovery [22] and >65% viable myocytes are necessary for postoperative improvement of myocardial dysfunction [23]. This correlates with the voltage amplitude of endocardial electromechanical mapping [17]. Accordingly, our study reveals improved unipolar voltage and a lower extent of histological fibrosis (8% vs. 28%) in the area at risk after EPO injection: the significantly reduced percentage of myocardial fibrosis and reduced intramyocardial depth of collagen fibers correlates with augmentation of the UV.

The mean ejection fraction remained unchanged in the EPO group, whereas it declined in the control group, albeit not significantly. The local linear shortening (LLS) in the area at risk deteriorated in the follow-up investigations in both groups. In the rat acute myocardial infarction model, a 50% reduction in infarction area was demonstrated [11]. These investigators gave EPO systemically (intravenous or intraperitoneal administration) just after or shortly before the ischaemic event. It is possible that cardioprotective effects of EPO are more pronounced in acute ischaemia or when given before or only hours after onset of the ischaemic event. Shi et al. [24,25] showed that EPO cannot further increase cardioprotection in severe chronic hypoxia compared with normoxic hearts because resistance to ischaemia (preconditioning) is already exhibited. These observations may explain the more pronounced cardioprotective effects of EPO in other acute myocardial infarction studies in rodents. In addition, cardioprotective effects of EPO are obviously based on anti-apoptosis, but the extent of apoptosis in hibernating myocardium is controversial and the rates of apoptosis vary between studies [26]. Besides methodological differences (specificity of the TUNEL assay, sensitivity of electron microscopy) apoptosis rates are particularly high after short-term hibernation [27]. In the ischaemic model of hibernating myocardium used here, myocardial apoptosis in the EPO and the control group was rare at week 6 (less than 0.001%, data not shown). However, we cannot exclude the possibility that apoptosis rates may have been higher at earlier time points, as we only examined the heart specimen once at week 6 after constrictor implantation. Cardioprotection of EPO by anti-apoptosis in our model can be assumed, but remains to be proven.

Elsasser et al. described hibernation as a "self-perpetuating vicious cycle", where inflammatory reaction leads to progressive fibrosis, if reperfusion is not obtained [28]. This is in accordance with our model showing a progressive ischaemic area by electromechanical mapping in the non-treated animals. So the cardioprotective effect of EPO could be more obvious if it is given at an even earlier time point after ameroid placement. Therefore, it remains to be determined which time point and which dosage is optimal to induce a more significant cardioprotective effect of EPO in chronic ischaemic heart disease.

An exact nominal value of unipolar voltage that allows discrimination between viable and non-viable myocardium could not be obtained in previous studies since there is a large overlap between values of viable and non-viable dysfunctional myocardium [29,18]. In contrast with these clinical investigations, in our experimental study we could prove that the ischaemic low-voltage myocardium detected by endocardial electromechanical mapping was not fibrotic to an extent corresponding to more than 50% of myocardial tissue in the histological analysis. Macroscopic assessment never showed signs of transmural scarring or aneurysm. We can, therefore, assume that the myocardium has recovery potential in regards to contractility. This is important because EPO cannot exhibit cardioprotective effects on non-viable myocardium.

Also, negative effects of EPO on the cardiovascular system are known. EPO can elevate blood pressure and the incidence of thrombosis [30]. Increases in haematocrit have been correlated to higher mortality rates in patients with ischaemic heart disease [31]. Although we did not draw blood samples weekly, in this study a single dose of locally delivered EPO did not contribute to haemoglobin or haematocrit elevation 4 weeks after EPO administration. This is consistent with the findings of Ehrenreich et al. who gave much higher doses of EPO (33.000 U per day intravenously for 3 days) in patients with acute ischaemic stroke [2]. In these patients haemoglobin increase was not observed.

In summary, after percutaneous endocardial EPO injection in the circumflex constrictor model we found a significant reduction in size of the expanding ischaemic area detected by electromechanical mapping. EPO attenuates the decrease of electric activity and the degree of corresponding histological fibrosis in the area at risk. Further studies are necessary to evaluate the effect of EPO in chronic ischaemic heart disease.


   Acknowledgments
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This work was supported by grants from Cordis Inc., Germany and the Werner-Otto-Stiftung, Hamburg, Germany.

We thank Detlev Hennigs for graphic design expertise and Sigrid Boczor for statistical analysis and Dr. Alice Alonso for reviewing the manuscript.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
1 Equally contributed to this article. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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