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Eur J Cardiothorac Surg 2002;22:733-737
© 2002 Elsevier Science NL

Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated ß-adrenergic signaling modulation

Hendrik T. Tevaearaia,c*, G. Brant Waltona, Andrea D. Eckharta, Janelle R. Keysa, Walter J. Kocha,b

a Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
b Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
c Department of Cardiovascular Surgery, University Hospital, (CHUV), rue du Bugnon 46, CH-1011 Lausanne, Switzerland

Received 13 March 2002; received in revised form 24 July 2002; accepted 26 July 2002.

* Corresponding author. Tel.: +41-21-314-2280; fax: +41-21-314-2278
e-mail: hendrik.tevaearai{at}chuv.hospvd.ch


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Reperfusion after myocardial ischemia goes together with alteration of the ß-adrenergic (ßAR) signaling. Especially the level and catalytic activity of ß AR kinase (ßARK1) are increased. We hypothesized that myocardial expression of a ßARK1 inhibitor (ßARKct) may protect from post-reperfusion dysfunction. Methods: Two groups of rabbits were treated by intracoronary delivery of either phosphate-buffered saline (PBS) or a solution of adenovirus carrying the ßARKct transgene (Adeno-ßARKct). At day 5, the hearts were explanted after cold cardioplegic arrest, and preserved at 4 °C for 4 h. Reperfusion was hemodynamically standardized on a Langendorff apparatus with oxygenated Krebs solution for 30 min before left ventricular (LV) pressure was recorded using an LV latex balloon connected to a pressure transducer. Non-arrested hearts immediately perfused on the Langendorff apparatus served as controls. Results: LV contractility (LV dP/dtmax, P<0.05) and relaxation (LV dP/dtmin, P<0.05) were reduced, and end diastolic pressure (LV EDP) was increased after prolonged exposure to cold preservation solution as compared to normal control hearts, both under basal conditions and when stimulated with the ßAR agonist isoproterenol. However, these parameters remained within a normal range in Adeno-ßARKct-expressing hearts arrested and preserved for 4 h. Biochemical analysis shows a reduced ßAR density and an impaired signaling after reperfusion of hearts arrested for 4 h whereas it is normalized in Adeno-ßARKct-expressing hearts. Conclusion: Myocardial gene-mediated inhibition of ßARK1 via ßARKct expression avoids ventricular dysfunction after prolonged preservation. Therefore, this may represent a way of improving early results of cardiac transplantation and perioperative function.

Key Words: Transplantation • Myocardial preservation • ß-Adrenergic receptor • Gene therapy • Heart failure


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Post-reperfusion contractile dysfunction is commonly observed following cardiac transplantation and accounts for significant early post-operative morbidity and mortality [1,2]. Ischemia–reperfusion-related myocardial injury plays a major role in those situations and the ß-adrenergic receptor (ß-AR) system appears to be critically involved in such functional alterations [3–5]. Similar to other forms of heart failure, the ßAR system is altered due to various membrane and cytoplasmic biochemical changes, all accounting for global myocardial desensitization [6,7]. One of the predominant mechanisms of desensitizing ßARs is through the action of G protein-coupled receptor kinases (GRKs) such as the myocardial ßAR kinase (ßARK1) [8]. This cytoplasmic enzyme phosphorylates only agonist-occupied ßARs after translocation from the cytoplasmic compartment to the membrane. In fact, translocation is due to a binding domain located on the carboxyl terminal (ct) portion of ßARK1 [9]. Recently, a peptide inhibitor of ßARK1 was generated based on the last 194 amino acids of ßARK1 (ßARKct), incorporating this entire binding domain but not the catalytic domain [10]. The ßARKct molecule has now demonstrated high potential in improving ventricular contractile function in various transgenic models of heart failure [11–13].

Myocardial signaling through ßARs is, however, the strongest way to increase inotropy. Therefore, although the quality of organ preservation and storage is critical, our hypothesis is that perioperative dysfunction may be alleviated by gene-mediated manipulation of myocardial ßAR signaling. We used gene transfer technology to investigate the effect of myocardial ßARKct transfection on LV function following cardioplegia and a prolonged period of cardiac preservation. We demonstrate that contractile function was significantly improved as compared to non-treated hearts when reperfused after 4 h of cold storage.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Adenoviral transgene and myocardial gene delivery
We used a second generation replication-deficient serotype 2 E1/E4 deleted adenoviral backbone for Adeno-ßARKct as previously described [14]. Solutions were prepared immediately before being injected by thawing aliquots of 5x1011 total viral particles (tvp) of Adeno-ßARKct and mixing it with phosphate buffered solution (PBS) to a final volume of 2 ml. Protocols were approved by the Animal Care and Use Committee of Duke University and all procedures were performed in accordance with the European Convention on Animal Care. New Zealand White rabbits ({approx}3 kg) were anesthetized with ketamine (60 mg/kg) and acepromazine (1.0 mg/kg), intubated and mechanically ventilated before a left thoracotomy was performed. The ascending aorta was freed from the pulmonary artery and clamped immediately before the adenoviral transgene solution was quickly injected into the left ventricular (LV) cavity as previously described (n=5) [14,15]. The aortic clamp was released after 45 s as we showed this clamping time allowed optimal gene expression with no noticeable myocardial damage in healthy hearts [16]. A comparison group included animals receiving 2 ml of PBS only and were randomized in a blind manner (n=5). Animals were then kept in separate cages and observed for 5 days.

2.2. Myocardial preservation, reperfusion and measurement of LV function
Animals were anesthetized using the same drug combination as above, intubated and ventilated before a clamshell incision was performed. After full anticoagulation with 1000 IU/kg of heparin, 30 ml of University of Wisconsin solution was slowly injected into the LV cavity while the ascending aorta was clamped and the inferior vena cava was transected. The hearts were then explanted and stored into 0.9% saline solution on melting ice. After 4 h, the hearts were hung on a modified Langendorff apparatus and perfused at a constant flow of 22 ml/min with modified oxygenated Krebs solution (NaCl 118 mM, KCl 4.7 mM, MgSO4 1.2 mM, KH2PO4 1.2 mM, NaHCO3 25 mM, dextrose 5.5 mM, CaCl 2.5 mM, EDTA 136 mg/l) at 37 °C allowing hearts to start beating within 1 min. A latex balloon was inserted into the LV cavity through the left atrium and mitral valve and connected to a pressure transducer (Millar Instruments, Houston, TX). Baseline end diastolic volume (LV EDV) was standardized by adjusting the balloon volume to give an end diastolic pressure (LV EDP) of 0 mmHg. After 30 min of warm reperfusion, LV functional assessment was performed by measuring LV pressures for an LV EDV augmented to ‘baseline+0.1 ml’. Response to stimulation with the ß agonist isoproterenol (Iso) was also studied. Results of Adeno-ßARKct-treated hearts and those which received PBS only were compared with control hearts obtained from normal rabbits with no prior surgeries, that were immediately perfused on the Langendorff apparatus after harvesting (n=4). Therefore, these control hearts were not arrested and did not suffer from ischemia as less than 1 min was necessary to harvest the heart and reperfuse it on the Langendorff apparatus.

2.3. Gene expression and biochemical analysis
At the end of the physiologic measurements, the hearts were maintained on the Langendorff apparatus and perfused for an extra 30 min to allow wash-out of the Iso. Confirmation of Adeno-ßARKct transfection was analyzed by Northern blot analysis using total RNA extracted from LV samples as previously described [14]. Density of ßARs was measured in LV membrane preparations by a radioligand binding assay using 300 pmol/l of [125I]cyanopindolol at 37 °C for 1 h with freshly prepared membranes as previously described [11,14]. Adenylyl cyclase activity was also assessed in LV preparations using 20 µg of membrane, incubated with 0.1 µmol/l [{alpha}-32P]ATP for 15 min at 37 °C as previously described [11,14]. Activity was measured under basal conditions or after co-incubation with 1 mmol/l Iso or 10 mmol/l sodium fluoride (NaF) to check for maximal adenylyl cyclase activity.

2.4. Statistical analysis
Data are presented as mean±SEM. Comparisons between each of the two groups and control animals were made using Student's t-tests. For all analysis, a value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Assessment of LV function was analyzed by measuring LV contractility (LV dP/dtmax) and relaxation (LV dP/dtmin) under standardized preload and afterload conditions. After 4 h of preservation in cold saline solution, reperfused hearts all demonstrated significant impairment in basal contractile function as shown by a 25–30% reduction of contractility and relaxation (Fig. 1) . However, basal contractility and relaxation in ßARKct-expressing hearts were not significantly changed as compared to normal control non-arrested hearts (Fig. 1). Similarly, stimulation with Iso was significantly impaired in PBS-treated hearts reperfused after cardioplegia and prolonged cold storage (Fig. 1) whereas hearts expressing the ßARKct transgene had a normal contractile response to Iso (Fig. 1). LV EDP in response to a 0.1-ml increase of LV EDV was almost doubled in hearts that received PBS 5 days prior to cold storage; however, it was within normal range or even below control values in hearts expressing the ßARK inhibitor (Fig. 2) . Heart rate was not significantly changed in either the PBS- or the ßARKct-treated hearts as compared to control non-cardioplegic hearts (Fig. 3) .



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  		Fig. 1. LV contractility (A: LV dP/dtmax) and relaxation (B: LV dP/dtmin) in hearts reperfused on a Langendorff apparatus after explantation and prolonged preservation (4 h) in cold saline solution before warm reperfusion. Results are obtained from hearts expressing ßARKct after adenoviral-mediated gene delivery (n=5) vs. sham-operated hearts that received PBS (n=5) and compared with Control hearts with no previous operations or treatments (n=4). Measurements are taken under standardized ‘baseline’ conditions where LV EDV was set as a volume giving an LV EDP of 0 mmHg augmented by 0.1 ml. Results are also presented for measurements taken under stimulation with Iso (0.33 µg/min). *P<0.05 (PBS vs. Control), {dagger}P<0.05 (ßARKct vs. PBS).

 


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  		Fig. 2. LV compliance as reflected by LV end-diastolic pressure (LV EDP) response to a 0.1-ml increase of LV end diastolic volume (LV EDV) in hearts expressing ßARKct (n=5) vs. hearts previously treated with PBS (n=5), isolated and preserved in cold saline solution for 4 h before warm reperfusion, and comparison with Control non-ischemic hearts (n=4). *P<0.05 (PBS vs. Control), {dagger}P<0.05 (ßARKct vs. PBS).

 


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  		Fig. 3. Heart rate in hearts expressing ßARKct (n=5) and hearts previously treated with PBS (n=5), isolated and preserved in cold saline solution for 4 h before warm reperfusion, and comparison with Control non-ischemic hearts (n=4).

 
ßARKct expression was confirmed by Northern blot analysis in each heart treated with the adenoviral transgene whereas no expression could be detected in any of the control hearts (Fig. 4) . Cardioplegic arrest with UW solution and cold preservation for 4 h lead to a significant decrease in ßAR density in PBS-treated hearts (Fig. 5A) . Conversely, ßAR density was not altered by prolonged preservation in ßARKct-expressing hearts as it remained within a normal range as compared to control hearts (Fig. 5A). More importantly, the adenylyl cyclase activity was improved in hearts previously treated with Adeno-ßARKct as compared to hearts previously treated with PBS (Fig. 5B). In fact, both basal function of the enzyme and its activity in response to stimulation with the ß-agonist isoproterenol were significantly reduced in hearts arrested with UW solution and stored in cold saline solution for 4 h. Maximal activity of the enzyme tested by direct stimulation with sodium fluoride (NaF) was also decreased as compared to normal control hearts (Fig. 5B). Conversely, hearts expressing ßARKct demonstrated a normal basal adenylyl cyclase activity as well as a normal response to Iso stimulation. In addition, maximal activity was also normal (Fig. 5B).



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  		Fig. 4. Representative Northern blot of ßARKct RNA in Adv.ßARKct-treated hearts as compared to hearts that received PBS only. +, positive control; -, negative control (water).

 


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  		Fig. 5. ßAR density (A) and LV adenylyl cyclase activity (B) measured in LV membrane preparations from hearts explanted and preserved ex vivo in cold saline solution before warm reperfusion. Comparison is made between hearts expressing Adeno-ßARKct (cross-hatched columns; n=5), hearts that received PBS only (white columns; n=5) and Control hearts immediately reperfused after explantation (black columns; n=4). A: *P<0.05 (PBS vs. Control), {dagger}P<0.05 (ßARKct vs. PBS). B: *P<0.05 (PBS vs. Control), {dagger}P<0.05 (ßARKct vs. PBS).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study demonstrates that a heart with ßARK1 inhibited can be safely explanted and preserved in cold saline solution for as long as 4 h without showing any evidence of functional alteration by the time it is reperfused. In fact, the two major LV contractile parameters, LV dP/dtmax and LV dP/dtmin, remained normal in hearts when reperfused on a standardized Langendorff apparatus provided they were expressing the ßARK inhibitor peptide ßARKct. Changes in LV EDP in response to a standardized LV EDV also remained in a normal range as compared to control normal hearts not exposed to cold cardioplegia. Conversely, LV function was severely altered in hearts that were treated with a placebo as both contractility and relaxation were reduced by approximately 25% as compared to normal hearts, and LV EDP was approximately doubled. Interestingly, results were similar in conditions where the hearts were stimulated with the ß agonist isoproterenol.

The benefit of inhibiting ßARK1 has been described previously for other models of cardiac dysfunction [3,14]. In fact, using transgenic mice overexpressing ßARK1, we initially highlighted the critical role of this kinase in the development of ventricular dysfunction [11]. In a reciprocal manner, mice expressing the ßARK inhibitor ßARKct have enhanced contractile function [11]. These results reinforced the concept that the role of the ßAR system in regulating myocardial physiology is critical. More recently, we adapted a technique for in vivo intracoronary adenoviral-mediated gene delivery in normal rodents as well as in animals with severe heart failure [14,15]. Using these models we were able to show that not only does ßARKct expression lead to increased LV contractile function in normal hearts, but more importantly, contractile function remains normal in various models of chronic heart failure [14–17] as well as in acute ischemic settings [5,18].

The present study focused on prolonged ex vivo cardiac protection before warm reperfusion, a situation typically observed with donor hearts. In fact, the situation we reproduced with our model can be extrapolated to any models of ischemia–reperfusion, the commonest being cold cardioplegia for open-heart surgery. However, due to the significant morbidity-mortality rate related to altered myocardial function following transplantation, donor hearts represent an attractive target for modulating the ß-AR signaling. From another point of view, transgenes may be selectively delivered during the prolonged ex vivo period, thus allowing robust and widespread gene expression while avoiding contamination of other organs. Previous studies demonstrated that it is possible to increase contractile function of transplanted hearts by delivering, via the coronaries, a load of adenovirus carrying either the ß2AR or the ßARKct transgenes [19–21].

From a biochemical point of view, our data confirm results obtained in previous studies [5,14]. In fact, ßARKct prevents translocation of ßARK1 from the cytoplasmic to the membrane compartment of cardiomyocytes and therefore maintains normal signaling through G proteins as demonstrated by normal adenylyl cyclase activity. Interestingly, ßAR density was also normalized which certainly contributes to improved ßAR responsiveness.

Our study certainly has limitations including the fact that we used the Langendorff apparatus for measurement of LV contractile function. In fact, relaxation is impaired in reperfused ischemic hearts and consequently, the LV EDV used to standardize our basal conditions may not be similar in all three groups. However, although we confirmed the compliance defect in reperfused PBS-treated hearts, we demonstrated that ßARKct-expressing hearts had a normal response to increasing LV EDV. Also, because of the temporary effect of gene expression when using adenovirus as a vector, we could expect a reduced benefit at approximately 2–3 weeks following the gene delivery. This transient expression may, however, be considered advantageous since long-term expression is probably unnecessary. Temporary ßARKct expression in the heart may therefore be helpful for progression through the critical first days following cardiac transplantation or other reperfusion period following acute ischemia.

In conclusion, adenoviral-mediated gene delivery can be performed preventively in situations where we expect ventricular dysfunction associated with ischemia–reperfusion such as following cold cardioplegic cardiac arrest for open-heart surgery or transplantation. In particular, myocardial adenoviral-mediated ßARKct expression represents a novel way of improving contractile function in freshly reperfused hearts. Therefore, gene-mediated inhibition of ßARK1 or other chemical ways to do so may represent a new strategy for preservation of donor hearts.


   Acknowledgments
 
The authors thank K. Wilson, K. Campbell and K Shotwell for excellent technical assistance. This work was supported by grants from the Swiss National Science Foundation FN 3200-065044.01 and 84NP-057501 (H.T.T.), NIH grants HL59533 (W.J.K.) and HL 56205 (W.J.K.) and a research fellowship from the Howard Hughes Medical Institute (G.B.W.).


   Footnotes
 
Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.


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

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