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Eur J Cardiothorac Surg 2003;24:98-104
© 2003 Elsevier Science NL

Reproducible model of post-infarction left ventricular dysfunction: haemodynamic characterization by conductance catheter

A.K. Hasnata, Enno T. van der Veldeb, Jimmy K.F. Hona, Magdi H. Yacouba*

a Academic Department of Cardiac Surgery, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK
b Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

Received 21 June 2001; received in revised form 31 March 2003; accepted 4 April 2003.

* Corresponding author. Tel.: +44-20-7351-8533; fax: +44-20-7351-8229
e-mail: m.yacoub{at}ic.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: The understanding of pathophysiology and cellular mechanisms of chronic heart failure requires the creation of appropriate and accurately characterized animal models, thus enabling meaningful evaluation of evolving medical and surgical therapies. Methods: The left anterior descending and its diagonal branch were ligated in 12 sheep to induce left ventricular dysfunction. Results: Study of left ventricular pressure–volume loops 3 months post-operatively showed a significant deterioration of both systolic and diastolic indexes of left ventricular function. The left ventricular end-diastolic pressure increased from 3±1 to 7±1 mmHg (P<0.001) along with a substantial increase in end-diastolic volume from 78±8 to 121±6 ml (P=0.002) and a significant decrease in cardiac output from 2±0.2 to 1.5±0.2 l/min (P=0.001). The left ventricular end-systolic pressure–volume relationship deteriorated from 2.7±0.37 to 0.7±0.16 mmHg/ml (P=0.0002) along with a significant reduction in the pre-load recruitable stroke work (P=0.001). The ejection fraction decreased from 34±2% to 16±4% (P<0.001) with a significant decrease in +dp/dt and -dp/dt (P=0.009). The mean systemic blood pressure, however, was maintained due to a substantial increase in the systemic vascular resistance (P=0.007). Conclusion: This study describes a reproducible large animal model of left ventricular dysfunction. This model is potentially useful to study the pathogenesis of remodelling, surgical management of heart failure and development of novel treatment strategies.

Key Words: Sheep • Left ventricle • Ventricular dysfunction • End-systolic pressure–volume relationship • Pre-load recruitable stroke work


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Chronic heart failure (CHF) is the final common pathway of most cardiac diseases and represents a leading cause of mortality and morbidity worldwide [1]. Despite better understanding of the pathophysiology and cellular and molecular mechanisms that has grown over the past 30 years, this knowledge still remains incomplete; therefore, current medical and surgical therapies are far from optimal. Consequently, there is a continuing need to develop existing as well as novel treatment strategies. The use of reproducible large animal models of CHF would greatly facilitate this line of research.

The precise definition of CHF has been controversial. This has important implications for the development of an adequate animal model. The various definitions given over the last century have been based either on physiological or clinical criteria, or both, and conceptualized on cardio-renal, cardio-circulatory and neuro-humoral models [2]. For the purposes of validating comparisons between clinical trials The Task Force on Heart Failure of the European Society of Cardiology have recently published guidelines for the diagnosis of CHF [3]. However, because these are based on evidence of cardiac dysfunction and reversibility of symptoms with appropriate treatment, they cannot be fully applied for the purposes of reproducing the heart failure syndrome in animals. Therefore, we have used more objective parameters, which are established markers of CHF including those of myocardial contractility, especially the use of left ventricular pressure–volume relationship.

The ovine model of left ventricular aneurysm has been reported previously [4] the haemodynamics of which were later investigated in another study [5]. This model has been subsequently reproduced on the same principles to study left ventricular wall stress [6], ischemic pre-conditioning of the myocardium [7], neuro-humoral changes [8] and the effects of pharmacological and mechanical therapies after myocardial infarction [9–14]. The essential component of this model has been the acute ligation of left anterior descending coronary artery and its diagonal branch at a point 40% of the distance from apex to base [4,5].

Following a large myocardial infarct changes in the remaining viable myocardium are induced to produce a process of remodelling [15]. We hypothesize that larger size of the infarct is of critical importance in producing remodelling of the remaining myocardium and therefore the degree of heart failure [16]. We have investigated this model further by increasing the size of myocardial infarction, and studying its reproducibility and its acute and chronic effect on left ventricular pressure–volume relationship as studied by conductance catheter.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Induction of left ventricular failure
Fourteen Texal cross (breed) sheep with a mean body weight 30.1 kg (range 29–32 kg) were studied and cared for in accordance with guidelines laid down by the Home Office of Great Britain and Northern Ireland.

2.2. Premedication
All the animals were pre-medicated with an intramuscular injection of 200 mg Ketamine (Ketamine HCl 10 mg/ml) and 10 mg Diazepam (5 mg/ml; Roche).

2.3. Induction and maintenance of anaesthesia
General anaesthesia was induced through a mask with a mixture of 0–3% halothane and 10 l/min oxygen. The anaesthetic was maintained with gas mixture of 1.5–2% halothane, 10 l/min oxygen and nitrous oxide at 1 l/min throughout the procedure. A 2-cm-diameter orogastric tube was passed to enable decompression of the ruminant stomach.

2.4. Analgesia and antibiotic prophylaxis
Peri-operative analgesia was provided with Pethidine (0.25–0.5 mg/kg intravenously (i.v.)). Antibiotic cover was used as prophylaxis against procedure related acquired infections. Cefuroxime (750 mg; Zinacef, Glaxo) was given i.v. at induction and a dose of 600 mg oxytetracycline (oxytetrin 20 LA, Mallinckrodt Veterinary Ltd) was given intramuscularly (i.m.) at the end of surgery. Post-operative analgesia was provided with 5 mg/kg buprenorphine i.m. (Tamgesic, Reckitt and Coleman).

2.5. Surgical technique
2.5.1. Left thoracotomy
Antero-lateral thoracotomy incision was made and the thoracic cavity entered through the fifth intercostal. The pericardium was opened tangentially from level of the apex of the heart to beyond the pulmonary artery.

2.5.2. Measurement of haemodynamics
Haemodynamics were studied by measuring left ventricular pressure–volume relationship with the use of conductance catheter technique. The principles of this technique to estimate left ventricular volume have been previously described [17]. A small hole was made in the apex of the left ventricle and a 12-electrode conductance catheter with integrated pressure-sensor (Sentron, The Netherlands) was inserted along the long axis of the left ventricle, and the tip of the catheter was passed through the aortic valve into the ascending aorta and the aortic volume signals acquired through the distal segment. The conductance catheter was then pulled back gently into the left ventricle such that all five segments yielded good left ventricular signals thus making sure that the catheter lay along the left ventricular long axis with its tip just below the aortic valve. The conductance catheter was connected to a Leycom sigma-5DF signal-conditioner processor (CardioDynamics, Zoetermeer, The Netherlands). Its output was connected to a computer and acquired at 200 Hz. Data acquisition was performed using the conduct-PC software package (CardioDynamics). Measurement of blood conductivity ({sigma}b) needed for calibration is incorporated in the sigma-5DF, with a special cuvette to be filled with 4 ml of blood. This calibration was performed every half-hour and also after infusion of fluids which might have altered blood conductivity. The parallel conductance factor was estimated by injection of small amount (0.5–2 ml) of hypertonic saline (10%) into the pulmonary artery [17]. The right pleura was opened between the diaphragm and the left ventricular apex for access to the inferior vena cava and cardiac output measurements performed by pulmonary artery flotation catheter. Direct occlusion of the inferior vena cava was used to obtain end-systolic pressure–volume relationship (ESPVR). The slope of the ESPVR (Ees, end-systolic elastance) was used to quantify the left ventricular function. A minimum of five good runs without any interference or extrasystoles were recorded in each study. After acquisition of the data the conductance catheter was left placed in situ in the left ventricle for further studies during acute myocardial infarction.

2.5.3. Coronary ligation
The heart was lifted forward by placing a pack at the back and coronary anatomy defined. The left anterior descending artery (LAD) was ligated by 4/0 silk under running suture at a point approximately 50% of the distance from apex to base (atrio-ventricular groove) of the heart. The diagonal branch of the LAD was then ligated at a point that was approximately in line with the point at which the LAD was ligated. Complete ligation was confirmed by profound ECG changes, immediate dark blue discolouration of the affected myocardium, which was accompanied by dyskinesis of the infarcted area.

The left ventricular pressure–volume relationship was re-studied 15 min after coronary ligation and the conductance catheter was removed. In all cases patchy areas of atelectasis and some degree of pulmonary oedema were noticed in both lungs after coronary ligation. The left and right pleural cavities were drained through 32-F chest drains and the chest was closed after blocking the 3rd, 4th, 5th and 6th intercostal nerves with a 1.5-ml injection of marcain (10 ml amp 0.5% 1/200 000 adrenaline) (Bupivicaine/Adrenaline, Antigen Pharmaceuticals).

2.5.4. Arrhythmia prophylaxis
Ventricular arrythmias featured in all animals after coronary ligation. Prophylaxis with 100 mg lignocaine (lignocaine HCl 2% w/v, Antigen Pharmaceuticals 100 mg/5 ml) and 150 mg cordarone (amiodarone HCl 150 mg in 3-ml ampoules, Sanogi Winthorp) added to two different bags of 50 ml Hartman's solution were infused intravenously over 15 min after the conductance catheter measurements and before ligation of the coronary arteries. This resulted in a temporary drop of arterial blood pressure. In our experience it was vital to keep the mean arterial blood pressure above 70 mmHg during acute evolving myocardial infarction. This was maintained by slow infusion of metraminol (2 mg in 50 ml Hartman's) commenced before coronary ligation and continued till closure of the chest. An additional very slow infusion of 100 mg lignocaine and 150 mg amiodarone was commenced 20 min after ligation and maintained until the end of the procedure. No further anti-arrhythmic medications were used in the immediate or late post-operative period. In order to prevent pulmonary oedema, 20 mg of Lasix (frusemide 20 mg/ampoule) was given just before coronary ligation and another 20 mg dose repeated half an hour later.

2.6. Final assessment
Three months after the initial operation, all animals were anaesthetized, instrumented and monitored as before and the chest opened through a vertical median sternotomy incision. The left ventricular pressure–volume relationship was studied through the left ventricular apex as before. The animals were then euthanized while still under anaesthesia according to the Home Office regulations and the heart excised for gross, histological and molecular analysis.

2.7. Statistics
The measurements are reported as mean±SD. The differences between before infarction measurements and at subsequent times are compared by the paired t-statistics. The significance is accepted at P<0.05 probability.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
A total of 14 animals were included for this phase of the study. Two died on the operating table due to intractable ventricular arrhythmias after coronary artery ligation (mortality 14%). There were no deaths in the immediate post-operative period or during the remaining 12 weeks including at the re-operation.

3.1. Haemodynamics during acute evolving myocardial infarction
All the animals during acute evolving myocardial infarction showed an increase in both right and left side filling pressures (P<0.001). There was a significant rise in mean pulmonary artery pressure (P<0.001). The left ventricular end-diastolic pressure increased from 3±1 to 15±1 mmHg (P<0.001). The mean systemic arterial pressure was pharmacologically manipulated and kept above 70 mmHg by metraminol infusion to maintain adequate coronary perfusion to the residual viable myocardium. The heart rate decreased from 94±9 to 78±7 beats/min (P<0.01), following the administration of lignocaine and/or amiodarone even before coronary artery ligation.

The left ventricular pressure–volume loop measured 15 min after coronary ligation showed a shift upward (increase in left ventricular end-diastolic pressure) and rightwards (increase in left ventricular end-diastolic volume). The increase in left ventricular end-systolic volume thus resulted in a decrease in stroke volume and ejection fraction. The left ventricular stroke work significantly declined as shown in a decreased area of the pressure–volume loop. The shift to the right and change in the slope of the end-systolic pressure–volume relationship showed decreased contractility (Fig. 1) .



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  		Fig. 1. Left ventricular pressure–volume relationship before and 15 min after coronary artery ligation.

 
3.2. Haemodynamics after 12 weeks
In all animals macroscopically, large, dyskinetic, thin fibrous apical aneurysms had formed distal to the coronary ligation site showing transmural myocardial infarction. A mean of 28±2% of the left ventricle had transmural infarction leading to full thickness involvement of the left ventricular apex, distal two-thirds of inter-ventricular septum and the left ventricular free wall.

A significant increase in the pre-load was seen in all animals 12 weeks after myocardial infarction. This was documented by an increase in the right atrial pressure from 3±1 mmHg before coronary ligation to 6±1 mmHg (P=0.008). The pulmonary artery pressure increased from 12±2 to 17±1 mmHg (P<0.001). The left atrial and left ventricular end-diastolic pressures similarly increased from 4±1 to 8±2 mmHg (P=0.004) and 3±1 to 7±1 mmHg (P<0.001), respectively.

The systemic arterial blood pressure, however, was maintained as shown by mean arterial pressure of 85±11 mmHg before infarction to 77±20 mmHg 12 weeks after infarction, the difference being not significant (P=0.48). Cardiac output showed a significant decrease from 2±0.2 to 1.5±0.2 l/min (P=0.001) and the systemic and pulmonary vascular resistances increased from 1326±213 to 2743±779 dynes/cm2 and from 419±66 to 494±33 dynes/cm2 (P=0.005), respectively.

There was a significant deterioration in left ventricular systolic indices. The left ventricular end-systolic pressure–volume relationship shifted to the right and the slope decreased from 2.7±0.4 to 0.6±0.16 mmHg/ml (P<0.001) (Fig. 2) . Similarly, the pre-load recruitable stroke work (PRSW) showed a significant shift down and rightwards (Fig. 3) . This was accompanied by an increase in the end-diastolic volume from 78±8 to 121±6 ml. The left ventricular stroke work and ejection fraction decreased from 1490±132 to 520±100 g/m (P<0.001) and 34±2% to 16±4%, respectively. There was a significant decrease in positive and negative left ventricular dp/dt (P<0.001).



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  		Fig. 2. Left ventricular end-systolic pressure–volume relationship before and 12 weeks after coronary artery ligation.

 


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  		Fig. 3. Left ventricular pre-load recruitable stroke work before and 12 weeks after coronary artery ligation.

 
3.3. Rhythm manifestations
Commonly, short runs of self-limiting ventricular tachycardia and multiple ventricular ectopics were seen usually 20 min after coronary artery ligation. These subsided by use of 50-mg additional boluses of intravenous lignocaine. Persistent ventricular tachycardia and fibrillation was reverted by internal cardiac massage, bolus of lignocaine, metraminol, and sodium bicarbonate followed by internal DC shock.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In this study we have described an animal model with a consistent left ventricular infarct size of 28±2% which is a substantial increase in myocardial infarction of 22.9±2.5% previously reported in similar studies [4] and characterized the resulting left ventricular dysfunction using pressure–volume loops. We believe that increasing the size of transmural infarction plays an important role in producing remodelling of the remaining myocardium and therefore the degree of heart failure [15,16]. These findings are similar to and consistent with clinical and postmortem reports of heart failure in human's [18].

The ovine model of left ventricular infarction has a number of significant advantages. The sheep coronary anatomy is remarkably consistent and very similar to human coronary arterial circulation. The ovine heart as compared to other mammalian species reportedly lacks an intrinsic coronary collateral circulation [19]. Even in the presence of gradual coronary stenosis, there is no demonstrable growth of coronary collaterals [19]. This produces predictable and reproducible myocardial infarction with a small standard deviation after coronary artery ligation [4,19]. The sheep are widely available, relatively inexpensive, resistant to infection and easy to handle. Myocardial infarction in dogs after coronary artery ligation is inconsistent and unpredictable due to natural sub-epicardial collateral vessels [20,21]. Similarly, in calves the ventricular myocardium is sub-served by all three coronary arteries with abundant collaterals [22]. The coronary circulation in primates on the other hand is more similar to humans; however, higher cost, general unavailability and ethical considerations make their use prohibitive.

This study demonstrates a consistent deterioration of load-dependent diastolic indexes and importantly shows substantial deterioration in load-independent parameters of systolic function. All animals showed a decrease in cardiac output and increase in all the indices of left and right ventricular pre-load. The load dependent parameters of cardiac function such as left ventricular end-diastolic pressure significantly increased as shown in the upward movement of the loop. This was accompanied by a largely significant rightward shift of the loop depicting a large increase in the end-diastolic volume (Fig. 4) associated with a decrease in the negative dp/dt.



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  		Fig. 4. Left ventricular pressure–volume relationship before and 12 weeks after coronary artery ligation.

 
The results presented in this study aim to quantify global left ventricular function, and previous studies using conductance catheter and other methods have shown that the ESPVR, especially the shift in the position of the ESPVR, are sensitive indicators of global left ventricular function also with regional ischaemia [17]. The value of Emax given by the slope of the (linear) end-systolic pressure–volume relationship, which characterizes the intrinsic inotropic state or contractility of the myocardium, deteriorated in all animals (Fig. 2). The change in the value of Emax 3 months after myocardial infarction in this preparation is in contrast to previous studies [23]. We attribute this to the larger myocardial infarction, which produces significant remodelling of the remaining viable myocardium thus leading to a substantial deterioration of left ventricular systolic function. The impairment in left ventricular contractile function lead to a concomitant decrease in the stroke volume shown as a significant decrease in the width of the loop, thus resulting in increased end-systolic volume with an associated decrease in the positive dp/dt. There is also a significant deterioration of the left ventricular stroke work signified as a reduction in the total area of the pressure–volume loop.

The linear relationship between left ventricular stroke work and end-diastolic volume termed as pre-load recruitable stroke work has been proposed as a measure of left ventricular contractile state [17]. The PRSW is a more linear and more flexible index for evaluating contractile performance in the human ventricle when the conductance catheter is used [17]. The pressure–volume analysis showed a consistent deterioration of PRSW in this study and, importantly, the simultaneous decrease in both ESPVR and PRSW prove a substantial deterioration of the contractile state of the left ventricle (Fig. 3).

The mortality rates reported after experimental acute myocardial infarction in earlier era were as high as 70% [24], mainly due to intractable ventricular arrhythmias. Since then, however, the results have much improved and are attributable to factors such as better surgical and anaesthetic techniques, appropriate choice of animal species and definition of coronary anatomy, and more stringent management of arrhythmias and acute myocardial infarction.

Myocardial infarction causes regional changes in myocardial properties that continue to change as left ventricular remodelling occurs. After infarction there are regions of myocardium whose function varies from non-contractile to super-contractile as compared to pre-infarction in the short term. However, in the longer term, the non-infarcted myocardium undergoes a process of progressive ‘remodelling’ [25,26] which results in progressive heart failure. Remodelling involves the myocardial cells, the matrix, endothelial cells and fibroblasts with specific changes at cellular and molecular level [27]. Although these changes are ‘self-propelling’, recent strategies to reverse the process have been described [28–30]. The model described in this paper can be used to investigate the influence of different methods aiming at producing reverse remodelling including medical, surgical and combined strategies [28–31].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In this study we have characterized a model of severe left ventricular dysfunction by inducing a large myocardial infarct. Reproducible left ventricular systolic and diastolic dysfunction occurs with consistent results as shown by left ventricular pressure–volume relationship. This model is potentially useful to study the surgical and medical treatment of left ventricular failure. It lends itself to carry out a concomitant surgical procedure along with acute coronary ligation. Implantation of prosthetic or autologous surgical assist devices or gene therapy and/or cell transplantation [28–30] can be carried out during one surgical procedure and their efficacy can be evaluated during developing acute and chronic ventricular failure. This could be helpful in developing new and novel treatment strategies for reversal of severe heart failure.


   Acknowledgments
 
This work was funded by the British Heart Foundation and the Harefield Research Foundation. We thank Professor Colin Green and his team at Northwick Park Institute of Surgical Research for their technical assistance.


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

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K. M. Shioura, D. L. Geenen, and P. H. Goldspink
Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice
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