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Eur J Cardiothorac Surg 2001;19:41-46
© 2001 Elsevier Science NL

Pretreatment of human myocardium with adenosine

Harpreet Wasir, Anil Bhan, Shiv Kumar Choudhary, Rajesh Sharma, Sandeep Chauhan, Panangipalli Venugopal

Department of Cardiothoracic and Vascular Surgery, Cardiothoracic Sciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India

Received 3 May 2000; received in revised form 9 September 2000; accepted 19 October 2000.

Corresponding author. Tel.: +91-11-686-4851; fax: +91-11-686-2663
e-mail: anil_bhan{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objectives: While the role of adenosine pretreatment in animals has been well established, the role in humans has been controversial. We performed this prospective, randomized study to find out the usefulness of adenosine pretreatment in humans. Patients and methods: Twenty patients undergoing coronary artery bypass surgery for severe triple vessel disease and left ventricular dysfunction (ejection fraction<35%) formed the study population. The adenosine group (n=10) received adenosine infusion (200 µg/kg) before aortic cross-clamp. The control group (n=10) received only normal saline injection. Cardiac function indices were assessed post-operatively. Results: In the adenosine group there was a significant increase in cardiac output in the post-operative period from 3.46±1.06 to 4.46±0.92 l/min (P<<0.05). The cardiac index increased significantly in the adenosine group from 1.97±0.43 to 2.54±0.5 l/min per m2 (P<<0.05) and even when compared with the control group this increase was significant (adenosine group vs. control group, P=0.03). Systemic vascular resistance fell from 1898.8±558.4 to 1134.9±530.7 dyne/s per cm-5 (P<<0.05) in the adenosine group. The pulmonary artery wedge pressure fell significantly in the adenosine group from 11.1±5.0 to 7.2±2.6 mmHg (P<<0.05). Patients in the adenosine group maintained a lesser increase in resting heart rate post-operatively (96.1±13.4 to 114.1±18.7 beats/min) (P=0.7), as compared to the control group where the increase in the heart rate was significant (77.1±8.3 to 109.7±14.9 beats/min) (P<<0.05). In the adenosine group only one patient (10%) had a raised creatine phosphokinase (MB) level at 12 h post-operatively as compared to three patients (30%) in the control group (P<0.05). Conclusions: Adenosine pretreatment appears to protect against reperfusion injury in human hearts and thus results in improved post-operative haemodynamics.

Key Words: Adenosine • Reperfusion injury • Myocardial protection • Cardiopulmonary bypass


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Patients with coronary artery diseases have variable degrees of myocardial ischaemia. Despite the present day improved cardioprotective techniques, post-coronary artery bypass ventricular dysfunction remains an important cause of mortality and morbidity. No intervention has yet been proven to prevent reperfusion-mediated injury, ventricular arrhythmias and ventricular dysfunction after an ischaemic injury. Myocardial dysfunction after an ischaemic episode was thought to be associated with a low level of high energy phosphate production and utilization, inadequate myocardial perfusion, free radical injury and an alteration in calcium metabolism [1]. It has been well documented that administration of exogenous adenosine protects the heart by different mechanisms including the activation of A1 receptors and adenosine triphosphate (ATP)-sensitive potassium channels. Adenosine enhances the tolerance of myocardium to ischaemic arrest and improves cardiac contractility after a period of hypoxia. Nucleotide precursors lost during ischaemic episodes limit ATP recovery during the period of reperfusion. Thus, the concept of ATP preservation to reduce ischaemic injury became very important [2]. Various animal studies revealed a direct effect of adenosine to be the enhancement of ventricular function [3]. The main purpose of this prospective, randomized study was to evaluate the protective role of adenosine as a preconditioning agent in patients undergoing surgical myocardial revascularization in the presence of severe triple vessel disease (TVD) and impaired left ventricular function. In a small pilot study, we found that injection of adenosine (200 µg/kg) over a period of 1 min prior to aortic cross-clamp does not produce any haemodynamic instability.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Patient selection
Twenty patients undergoing elective coronary artery bypass surgery (CABG) for TVD and who had poor left ventricular function formed the study group. By definition these were the ones with an ejection fraction (EF) of <35% (assessed by echocardiography/ventriculography), regional wall motion abnormalities (assessed by ventriculography/echocardiography) and left ventricular end diastolic pressure of >25 mmHg (assessed by cardiac catheterization). With the help of a random number table, patients were randomized into two groups. The adenosine group (n=10) received adenosine pretreatment, whereas the control group (n=10) did not receive any adenosine. The patients in both groups were comparable (Table 1).


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  		Table 1. Comparison of preoperative parametersa

 
2.2. Preoperative evaluation
All patients had undergone coronary angiography and left ventricular angiography prior to admission. Stenosis exceeding 70% of the luminal diameter in one or more projections was considered haemodynamically significant which required surgical intervention. EF was estimated from left ventriculogram and was counter checked using transthoracic echocardiography. All patients underwent a complete haematological, biochemical and coagulation parameter assessment prior to surgery.

2.3. CABG technique
CABG was performed electively in all patients by a single surgeon (AB). After induction of anaesthesia the chest was opened via mid-sternotomy. CABG was performed using moderate hypothermia at 28°C. During cardiopulmonary bypass (CPB) a non-haemic prime and a bubble oxygenator with a calculated pump flow of 1.8–2.4 l/m2 were used. St. Thomas cardioplegia with blood as a carrier was used, and was delivered at 4–8°C antegradely. All distal anastomoses were done on the cardioplegic heart and all proximal anastomoses were done on a side-clamped aorta with the heart beating.

2.4. Adenosine administration
In the adenosine group, 200 µg/kg adenosine was injected via the pulmonary artery port of a Swan Ganz catheter as a rapid infusion over a period of 1 min prior to aortic cross-clamp and cardioplegia administration. The control group received an intravenous saline (0.9%) bolus injection.

2.5. Intraoperative and post-operative haemodynamic measurement
Haemodynamic data were collected prior to the onset of the bypass and after the patient was weaned off the bypass. Arterial blood gas and systemic arterial pressures were obtained using an invasive arterial line. Continuous cardiac output (CCO), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), left and right ventricular stroke work index (LVSWI, RVSWI), stroke volume (SV), continuous cardiac index, systemic and pulmonary vascular resistance index and stroke volume index were obtained by using a CCO monitor which was attached to a CCO thermodilution catheter (Baxter Edward Swan Ganz, Thermodilution Catheter (CCO/SVO2) Model 744H-7.5F, 139H-7.5 F). The mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP) and central venous pressure were also obtained. The intraoperative post-bypass readings were noted immediately after termination of CPB (0 h) and thereafter every 6 h up to 24 h post-operatively in the intensive care unit. Inotropes such as dopamine were only started if required based on the haemodynamic status post-operatively.

2.6. Statistical analysis
The continuous and interval-related variables were expressed as the mean±SD and the categorical variables were expressed as percentages. Fisher's exact test was used for comparison of nominal data. For within group comparisons, two-way ANOVA for repeated measurements followed by post-hoc comparisons using the Bonferroni multiple comparison test was performed. Similarly, to compare the adenosine group and the control group, an ANOVA for repeated measurements was performed followed by post-hoc comparisons using the multiple range test.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Operative variables were comparable in both groups (Table 2). No mortality was observed nor was there any intraoperative or post-operative complication in either group. There was no pre-bypass difference in any parameter between the two groups. The summarized intraoperative haemodynamic measurements are shown in Tables 3 and 4. In the control group there was no significant change in the cardiac index post-bypass. In the adenosine group, however, the cardiac index improved significantly from 1.97±0.43 to 2.54±0.5 l/min per m2 (P<<0.05) after completing the revascularization procedure. In the control patients the heart rate increased significantly from 77.1±8.3 to 109.7±14.9 beats/min (P<<0.05) post-operatively. There was a significant fall in the PVR as well as the SVR in both the groups. LVSWI and RVSWI improved in both the groups and the increase in the adenosine group was significant. No significant change was observed in MPAP; however, there was a significant fall in PAWP in the adenosine group from 11.1±5.0 to 7.2±2.6 mmHg (P<<0.05). The mean arterial pressure was significantly low in the control group post-operatively as compared to the adenosine group. The number of patients with post-operative creatine phosphokinase (MB) values at 12 h exceeding preoperative values by >50 U/l was significantly higher in the control group (three of ten (30%) in the control group vs. one of ten (10%) in the adenosine group) (P<0.05). Dopamine up to 10 µg/kg per min was needed in two of ten (20%) patients in the adenosine group, which was continued up to 7.36±0.45 h post-operatively, and in five of ten (50%) patients in the control group, which was continued up to 14.6±1.02 h post-operatively (P<0.01).


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  		Table 2. Comparison of operative parametersa

 

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  		Table 3. Comparison of intraoperative pre- and post-bypass haemodynamic variablesa

 

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  		Table 4. Comparison of significance (P value) of haemodynamic variablesa

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The term ischaemic preconditioning was coined by Murry et al. in 1986 [4]. Prior ischaemic exposure made the myocardium more tolerant to subsequent prolonged ischaemic episodes. Preconditioning has been reported in various animal studies [4]. Murry et al. [4] who originally described protection against infarction, noted that dogs subjected to four 5 min episodes of complete coronary artery occlusion interspersed with reperfusion paradoxically sustained smaller infarcts when subsequently subjected to 40 min of complete occlusion. There is now evidence indicating that the human heart can be preconditioned [5,6]. Adenosine has been thought to be responsible for the preconditioning as its beneficial effects could be prevented by pretreatment with adenosine receptor antagonist 8 – sulfophenyltheophylline [7]. Thus, it can be implicated that endogenous adenosine could be responsible for preconditioning.

Preconditioning has been seen to be beneficial by reducing the infarct size and preventing arrhythmias [8]. It has also been shown to reduce myocardial acidosis and protect against post-ischaemic contractile dysfunction. Deutsch et al. [9] examined 12 patients undergoing percutaneous transluminal coronary angioplasty and reported functional and metabolic adaptation during serial balloon inflations. This was attributed to ischaemic preconditioning of the myocardium which was caused by the narrowed lumen of the vessel and prior exposure to ischaemic episodes in the form of angina. The variables observed were the relief of chest discomfort, reduction in ST segment elevation, decreased pulmonary artery pressures and reduction in myocardial lactate production after subsequent balloon inflations. Results indicated improved myocardial function at the subsequent dilatations possibly attributed to the preconditioning caused by ischaemia of the myocardium. Thus, the preceding period of ischaemia prepared the myocardium and made it more adaptable for subsequent ischaemic episodes. Similarly, it has been observed by Kloner et al. [10] in a retrospective analysis that patients who experienced angina 48 h before infarction had smaller infarcts and a more favourable outcome compared to patients who did not have angina before myocardial infarction. Therefore, the hypothesis that the transient episode of ischaemia releases adenosine which then mediates the protective effect against ischaemic reperfusion injury is attractive.

Early reperfusion remains the most effective way of reducing the infarct size and improving ventricular function in experimental models and humans [1]. However, potential deleterious effects have been associated with reperfusion injury. ATP is rapidly degraded during myocardial ischaemia and purine by-products including adenosine are washed out during reperfusion, resulting in further nucleoside depletion [11]. Attention has been focused on the pathophysiology of myocardial ischaemia with subsequent reperfusion and methods of reducing reperfusion injury and associated reversible post-ischaemic dysfunction of ventricles [12,13]. Ventricular dysfunction after an episode of ischaemia has been termed as myocardial stunning as compared to irreversible injury which is a consequence of myocardial infarction. A stunned myocardium shows a defect in the myocardial cell volume, loss of nucleotides and ventricular contractile dysfunction [14–16]. The possible mechanism of ventricular dysfunction included a depressed level of ATP for hours to days after an ischaemic episode wherein there occurs a rapid mitochondrial ATP hydrolysis [17]. There also occurs an inability of the myofibrils to utilize energy. It is also associated with the generation of oxygen free radicals from activated neutrophils and from endothelium. These oxygen free radicals including superoxide anion (O2-), hydroxy radical (OH-) and hydrogen peroxide (H2O2) are highly reactive and are responsible for membrane lipid peroxidation and enzyme denaturation. Ischaemia results in a net depletion of ATP in the myocardial cells [18,19]. There is a delay in the de novo nucleotide synthesis resulting in low levels of adenosine, inosine and hypoxanthine because of their rapid washout from the tissue on reperfusion [20]. Thus, any agent which could be used to increase the depleted stores of ATP could aid in recovering post-ischaemic myocardial ventricular function. The efficiency of adenosine as a substrate for myocardial nucleoside formation was first demonstrated by Isselhard et al. [21,22]. His studies showed a 21–48% increase in levels of ATP after adenosine infusion into the heart of various animals. Adenosine has been shown to reduce ATP degradation during ischaemia and to enhance post-ischaemic ventricular function in crystalloid perfused and blood perfused hearts.

The cardioprotective effect of adenosine is well known. Adenosine delays the onset of ischaemic contracture, enhances post-ischaemic function and reduces infarct size. All these effects of adenosine are mediated via ADO A1 receptors located on the myocytes [23]. Cohen et al. [24] conceptualized hyperpolarization of the myocyte membrane during ischaemic arrest. They found improved ventricular function using hyperpolarized cardioplegic arrest using a potassium ATP channel agent. The transmembrane ionic gradients, the cellular integrity and the intracellular energy stores were all preserved. Adenosine pretreatment is well known to cause hyperpolarization by activation of outward potassium current, inhibition of inward calcium current and activation of specific A1 adenosine receptors. Adenosine released by ischaemic myocytes has a protective effect when infused before ischaemia. This concept of pretreatment in various experimental and clinical settings has prompted the cardiac surgeons to implement a similar therapeutic concept in patients undergoing open heart surgery. Lee et al. [25] demonstrated an improved cardiac index in adenosine-treated patients. Although ischaemic preconditioning has well documented protective effects, there are conflicting results on its beneficial effects in post-ischaemic function. The scientifically documented evidence regarding the pretreatment of human myocardium is scant. Further studies have to be undertaken to be sure of the beneficial role of ischaemic pretreatment in all varieties of open heart surgery.

Keeping in mind that adenosine is a strong mediator of myocardial pretreatment we selected a group of patients in whom the possible beneficial result of adenosine could be observed. Based on this premise we pretreated the human myocardium of these patients who were to undergo coronary bypass surgery for coronary artery disease with the background of impaired left ventricular function.

The major results of this study showed that the patients who were pretreated with adenosine prior to aortic cross-clamp and the onset of myocardial ischaemia (1) had improved indices of intraoperative and post-operative ventricular performance as indicated by improved cardiac output, cardiac index, SV, LVSWI and RVSWI and a fall in PAWP (2) had lowered post-operative indices of myocardial demand as shown by a lesser increase in the heart rate; (3) required lesser ionotropic support post-operatively, and (4) experienced less myocardial injury post-bypass as indicated by a reduced release of creatine phosphokinase (MB). Adenosine is a well known pulmonary vasodilater and, as expected, it caused a fall in MPAP and PVR. A fall in PVR could itself be responsible for an improved right ventricular diastolic function as indicated by a significantly raised RVSWI in the adenosine group. Although we did not measure the interstitial adenosine levels, we believe that direct adenosine infusion via the Swan Ganz catheter in the doses used did successfully achieve high myocardial concentrations adequate enough to cause myocardial pretreatment. As mentioned, LVSWI is an index of left ventricular performance and pulmonary capillary wedge pressure (PCWP) is an index of left ventricular diastolic function. With an improved left ventricular diastolic function there will be a significant fall in PCWP as evidenced by our results. This in turn will also have an indirect effect on the right-sided ventricular function which also improves. Therefore, myocardial protection with adenosine pretreatment appears to be a biventricular phenomenon. This is evidenced by an increase in the mean arterial pressure in the adenosine pretreatment group and a lesser requirement of inotrope post-operatively. Although the heart rates post-operatively in the control group were significantly higher, this is probably a reflection of the higher number of patients requiring dopamine up to 10 µg/kg per min, resulting in observed tachycardia. However, tachycardia due to inadequate cardiac output cannot be ruled out. Creatine phosphokinase (MB) was measured to assess the degree of myocyte injury. It was evident from the results that adenosine pretreatment protected the myocardium against reperfusion injury. Adenosine resulted in only one patient having levels of >50 U/l in the post-operative period, thus indicating lesser myocardial injury and adequate pretreatment.

Our study was very similar to various other studies which showed that pretreatment with adenosine improved the cardiac index in the post-operative period. Our patients showed improved indices of ventricular performance using adenosine pretreatment as seen by an increase in SV, LVSWI and RVSWI in the post-operative period. These variables were used as end-points to assess the benefits of adenosine in the post-operative period.

To conclude, the pretreatment of human myocardium before producing myocardial ischaemia results in improved indices of biventricular function after the termination of CPB and for the next 24 h in patients undergoing myocardial revascularization for coronary artery disease in the presence of impaired left ventricular function.


   Acknowledgments
 
This work was partly supported by an educational grant from the Baxter Health Care Corporation.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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