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European Journal of Heart Failure 2003 5(5):591-598; doi:10.1016/S1388-9842(03)00103-X
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© 2003 European Society of Cardiology

A porcine model of ischemic heart failure produced by chronic placement of a tube in a coronary artery

Sadanori Ohtsukaa,*, Kimito Ishikawaa, Syoji Suzukia, Iwao Yamaguchia, Noriyuki Masudab, Koichi Wadab and Wataru Uchidb

a Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba 1-1-1 Ten-noudai, Tsukuba-shi, Ibaraki-ken 305-8575, Japan
b Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. Tsukuba 305-8575, Japan

* Corresponding author. Tel.: +81-29-853-3210; fax: +81-29-853-3143. E-mail address: otk-sa{at}md.tsukuba.ac.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background and Aims: Animal models of heart failure (HF) are useful to clarify the mechanism and to develop therapeutic interventions. To produce an easy ischemic HF model, we induced myocardial infarction (MI) in pigs by placing a tube in the coronary artery.

Methods: Twelve pigs underwent echocardiography and were randomly allocated to the myocardial infarction group (MI group) and the control group. In the MI pigs, a 4.2 F nylon tube was placed via the carotid artery in the left circumflex coronary (LCx) artery to induce MI. Three months thereafter, thoracotomy was performed in the both groups and left ventricular (LV) pressure–volume relation was evaluated.

Results: Body weight, LV dimension and function did not differ in the baseline state between the two groups. Three months after the tube placement, LV diameter was larger (47±3 vs. 42±2 mm) and its fractional shortening was lower in the MI group than the control group. In addition, aortic flow was decreased, LV ejection fraction was decreased (25±5 vs. 52±6%) and LV diastolic pressure was elevated (14±3 vs. 8±2 mmHg) in the MI group compared with the control group. The extent of MI was 26±5% of the LV in the MI pigs.

Conclusion: The method of placing a tube in the coronary artery does not need thoracotomy or an additional procedure and enables the production of an ischemic HF model of pigs.

Key Words: Myocardial infarction • Coronary artery • Heart failure • Left ventricular function • Animal model • Pigs

Received September 11, 2002; Revised March 21, 2003; Accepted June 16, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure (HF) is a common syndrome of advanced heart disease. Despite much research and therapeutic development, HF is associated with high rates of morbidity and mortality and is a major health problem [1,2]. The available clinical interventions and the confounding effects of treatment, as well as restrictions due to ethical aspects are limitations to investigate the details of HF in humans. Since the early stage of HF may be asymptomatic, the incomplete recognition of its early process adds to its complexity. To supplement those limitations in approaching HF in humans, animal models play important roles to describe the disease processes and to develop treatments in HF.

A variety of methods has been used to produce models of HF [3,4]. Some methods used are rare or absent in humans, e.g. tachycardia-pacing induced HF, toxic cardiomyopathy, direct current shock models and others. However, animal models are preferred to be produced by the methods recreating the origins of HF in patients and should closely mimic HF in humans. Therefore, models of myocardial infarction have been commonly used, which is the main cause of the human HF and is associated with ventricular dysfunction and remodeling. The difficulties involved in producing an ischemic HF model are controlling the actual area of myocardial infarction by occluding the coronary artery. A too large damaged area will result in ventricular fibrillation or in low survival; however, small infarcts with or without the development of coronary collaterals is insufficient to induce ventricular dysfunction [3,5].

In the present study, we report a porcine model of ischemic HF. To induce myocardial infarction, we placed a nylon tube via the carotid artery in the left circumflex (LCx) artery in pigs. Since pigs have poor coronary collaterals, placement of a tube in the coronary artery impairs coronary blood flow and induces myocardial infarction. This method does not require thoracotomy or an additional intervention, and enables the reliable production of an ischemic HF in pigs.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals and experimental procedures for producing myocardial infarction
Male pigs (Lamdrace/White F1), weighing 22–26 kg were sedated with an intramuscular injection of 25 mg/kg ketamine hydrochloride. The pigs underwent echocardiography with an ultrasound system (SSA-250A, Toshiba Inc., Tokyo, Japan) and were randomly allocated to two groups: the myocardial infarction group (MI group) and the control group. The pigs of the control group were then allowed to recover. The pigs in the MI group were further anesthetized with sodium pentobarbital (25 mg/kg intravenously), subjected to endotracheal intubation and ventilated using a respirator. To place a tube in the LCx artery, the neck of pigs in the MI group was incised under sterile conditions and the left jugular vein and the left carotid artery were cannulated for infusion of the drug or solvent and for inserting a guiding catheter into the aorta, respectively. After an intravenous administration of antibiotics, 500 mg of cefotetan (Yamatetan, Yamanouchi Pharmaceutical Co., Tokyo, Japan), a 4.2 F nylon tube, 25 cm in length (Hanaco Medical Co., Saitama, Japan) was placed via the carotid artery in the LCx artery using fluoroscopy (model WHA-10B, Shimazu, Japan), as follows: (1) the tip of a 7 F guiding catheter was placed at the ostium of left coronary artery and 500 mg of nitroglycerine was injected into the left coronary artery; (2) a 0.025-inch guidewire was inserted through the guiding catheter into the LCx artery; (3) the guiding catheter was extracted with the guidewire left in the LCx artery; (4) a 4.2 F nylon tube was advanced over the guidewire and was placed in the LCx artery; and (5) finally, the guidewire and the venous catheter were extracted. The fluoroscopic finding of the tube placed in the LCx artery is shown in Fig. 1. The tube was placed in the LCx artery, as the distal end of the tube was positioned at about the distal two thirds of the main stream of the LCx artery. The depth of the tube in the LCx artery was determined based on a previous study in dogs [6] and a preliminary study in pigs. The cervical incision was sutured and the pigs of MI group were also allowed to recover.


Figure 1
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  		Fig. 1 Fluoroscopic finding of the tube placed in the left circumflex (LCx) artery at right anterior oblique (RAO) projection of the heart. White arrows indicate tube placed in the LCx artery.

 
The experimental interventions and protocols employed in this study were approved by the Committee on Animal Experiments of the University of Tsukuba, and adhered to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. Animals in the laboratory received every consideration for their comfort, including appropriate anesthetics during the operation and veterinary care after the operation.

2.2. Measuring hemodynamics and left ventricular function three months after the initial procedure
After an interval of three months, pigs of the control and the MI groups were sedated with an intramuscular injection of 25 mg/kg ketamine hydrochloride and were returned to the laboratory. All the animals underwent echocardiography, then were anesthetized with sodium pentobarbital (25 mg/kg), intubated through a midline cervical incision and ventilated by a respirator. The right femoral artery and vein were isolated through the inguinal incision and were cannulated with a polyethylene catheter for measurement of aortic pressure and for volume replacement, respectively. A median thoracotomy was performed and the pericardium was opened. An electromagnetic flow probe (FJ type 18 mm in diameter, Nihon Koden, Tokyo, Japan) was positioned around the ascending aorta for measurement of the aortic flow. The proximal portion of the left anterior descending coronary (LAD) artery was also dissected free and was surrounded by an electromagnetic flow probe (FJ type 3.0 or 3.5 mm in diameter, Nihon Koden) for measurement of LAD flow. A 6F-calibrated micromanometer (MPC-500, Millar Instruments, Huston, TX, USA) was placed in the left ventricle (LV) through the apex for recording of LV pressure. A 7F conductance volume catheter (2-RH-806, Leycom, Oegstgeest, The Netherlands) was also advanced to the LV through the apex with the most proximal electrode placed within the LV wall. The pacemaker leads were implanted in the right atrial appendage. A snair occluder was placed around the inferior vena cava for its transient occlusion. The schematic diagram of the experimental preparation is shown in Fig. 2.


Figure 2
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  		Fig. 2 Schematic diagram of the experimental preparation.

 
The flow probes were calibrated and connected to electromagnetic flowmeters (MFV-2100/3200, Nihon Koden). The analog signals including the measurements of aortic pressure and flow, LAD flow, and LV pressures were recorded on a compatible computer (Power Macintosh 8100/100AV, Apple Inc., Cupertino, CA, USA) with available hardware and software (MP100 and Acknowledge, Biopac Systems Inc., Santa Barbara, CA, USA). The conductance catheter was connected to a signal conditioner-processor (Sigma-5-DF, Leycom) to compute the LV volume and was also recorded on the computer with hardware and software using a software package (PVL Analysis, Physio-Tech, Tokyo, Japan).

Confirming that the hemodynamic variables were stabilized, steady state hemodynamics and LV pressure–volume loops were measured. After the baseline measurement was performed, the inferior vena cava was transiently occluded by constricting the snair to determine the LV end-systolic pressure–volume relationship. The transient vena cava occlusion was repeated in triplicate. At the end of the experiment, the animals were killed with an overdose of pentobarbiturate and the hearts were excised for pathological observation.

2.3. Data analysis
2.3.1. Echocardiographic measurement
Two-dimensional echocardiography images were obtained through the right intercostal space of the thorax and the views of the LV were recorded. At the chorda tendinea level, the LV short-axis diameter was obtained as a line connecting the midseptum and the midpoint of the posterior wall between the two-papillary muscles. The interventricular septal wall thickness and the posterior wall thickness were also measured. End-diastole was defined at the timing of the R wave on the ECG. End-systole was defined when the interventricular septal thickness was maximal at the timing of the terminal site of the T wave on the ECG.

2.3.2. Measurement of left ventricular volume and contractility
The conductance catheter utilizes the change in the electrical impedance with the alteration in the LV blood volume and was used for the continuous measurement of LV volume [7,8]. LV pressure–volume relations were determined simultaneously by the conductance catheter attached to signal conditioner-processor and the micromanometer transducer placed in the LV. After placement of both the conductance and micromanometer catheters, blood resistivity was measured and entered into the signal coordinator and volume correction was performed. An analog signal of the LV volume from the Sigma-5-DF and the LV pressure were converted into digital form at 200 Hz using the hardware (MP100, Biopac Systems Inc.) and collected on the computer using the software package (Acknowledge, Biopac Systems Inc.). LV pressure–volume loops, LV systolic and diastolic pressures, stroke volume, and stroke work were derived using this system.

The LV end-systolic pressure–volume relationship was measured by occluding the inferior vena cava with the snair. Analog tracings and the derived pressure–volume loops during the vena cava occlusion are shown Fig. 3. Fifteen subsequent cycles during an inferior vena cava occlusion with falling LV pressures and volumes were analyzed. End-systole was defined at the time of the peak instantaneous ratio of LV pressure to volume, and end-systolic data from each caval occlusion were fitted by linear regression analysis using the least square method. This relationship is described by the equation:


Formula

where Pes and Ves are the end-systolic LV pressure and volume, Vo is the volume axis intercept, and Ees is the slope of the end-systolic pressure–volume line. Ees is an index of ventricular contractility, and is relatively independent of preload, afterload and heart rate within the physiological ranges [9–11]. Ees was determined using the method described by Kass et al. [12]. End-diastole was determined at the point of onset of mechanical systole, which is identified as a point at the lower right corner of the pressure–volume loop.


Figure 3
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  		Fig. 3 Recordings of left ventricular pressure–volume diagram during inferior vena caval occlusion in a pig of control group (upper panel) and in a pig of myocardial infarction (MI) group (lower panel) three months after the initial procedure. A rightward shift of the end-systolic pressure–volume relation and a decrease in the slope of the end-systolic pressure–volume relation (Ees) were shown in the pig with MI. Vo is the volume axis intercept.

 
2.3.3. Pathological observation
The heart was excised, the atria and the right ventricle were removed and the LV was weighed. The tube was confirmed to be placed in the LCx artery and the proximal site of the LCx artery was excised for pathological observation. To detect the extent of scar tissue, the LV was sliced into 1-cm-thick sections, vertical to its long axis and each section was pictured by a digital camera (FinePix 2900Z, Fuji Photo Film Co., Tokyo, Japan) and recorded on a computer. The length of scar tissue and non-infarcted muscle for both the endocardial and epicardial surfaces of each histological section were measured by tracing on the obtained images with a commercially available graphic-analysis package (SigmaScan Pro 5.0, SPSS Inc., Chicago, IL, USA). The lengths of scar for the endocardial and epicardial circumferences for all histological sections were numerically summed, as were the endocardial and the epicardial surface circumferences. The ratio of the sum of lengths of the scar and surface circumferences is defined as the infarct size for each of the myocardial surfaces. Final infarct size was expressed in a percentage as the average of the infarct sizes of the endocardial and the epicardial surfaces times one hundred.

2.4. Statistics
All the results are expressed as means±S.D. Differences in echocardiographic, hemodynamic and LV measurements were analyzed by the two-tailed unpaired t test between the control and the MI groups. All statistical comparisons were performed with a commercially available statistical package for the Macintosh personal computer (StatView, version 5.0, SAS Institute Inc., Cary, NC, USA). The statistical significance was defined at a P value less than 0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Echocardiographic findings
Echocardiographic findings are shown in Table 1. Body weight, LV dimension and wall thickness did not differ in the baseline state between the control and the MI groups. At three months after the initial procedure, LV diameter was greater in the MI group and the wall thinning and the impaired wall motion was observed in the infarcted LCx area of the MI pigs. The representative echocardiograms of a control pig and an MI pig are shown in Fig. 4.


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  		Table 1 Echocardiographic data of the two groups

 


Figure 4
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  		Fig. 4 Echocardiograms of the short-axis view of the left ventricle (LV) in a control pig (upper panel) and in a pig with myocardial infarction (lower panel) three months after the initial procedure. M-mode and two-dimensional recordings are shown. Compared with control pigs, LV diameter was increased and the thinning and the impaired wall motion in the infarcted left circumflex (LCx) area were observed in the pigs with infarction.

 
3.2. Hemodynamic findings and left ventricular function
Hemodynamic findings and LV function three months after the initial procedure are shown in Table 2. Heart rate was similar and aortic pressure did not differ between the control and the MI groups. Aortic flow was decreased and systemic vascular resistance was increased in the MI group. LV volume and diastolic pressure were increased, and the LV ejection fraction was decreased in the MI group. As representative recordings of LV pressure–volume diagram during inferior vena cava occlusion in a control pig and an MI pig are shown in Fig. 3, a rightward shift of the end-systolic pressure–volume relation and a decrease in the slope of the end-systolic pressure–volume relation (Ees) were confirmed in the MI pigs.


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  		Table 2 Hemodynamic and left ventricular functional data of the two groups

 
3.3. Pathological observation
In all MI pigs, the LCx artery was confirmed to be occluded at its proximal site by fibrous tissue surrounding the placed tube. Microscopic observation showed that intimal proliferation and fibrous tissue occluded the LCx lumen around the tube (Fig. 5). Massive transmural infarction was observed in the LCx area of the MI pigs, as shown in Fig. 6. The percentage ratio of the surface area of necrosis against the whole LV was 26±5% (ranged from 20 to 33%). LV weight was increased in the MI group compared with the control group (106±10 g vs. 88±3 g, P<0.01).


Figure 5
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  		Fig. 5 Histopathological finding of the occluded left circumflex (LCx) artery in a pig with myocardial infarction (MI). A diffuse intimal thickening consists of numerous macrophages and large numbers of intimal smooth muscles surrounded by variable amounts of connective tissue.

 


Figure 6
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  		Fig. 6 Pathological finding of the left ventricle (LV) in a pig with myocardial infaction. LV was sliced into 1-cm-thick sections vertically to its long axis and the section at the papillary muscle level is shown. Areas of infarction are indicated by arrows.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
To produce a large animal model of HF, we placed a nylon tube in the LCx artery of the pigs and evaluated hemodynamics and LV function of this model. The pigs with the tube placed, showed LV remodeling and dysfunction, increased LV filling pressure and low cardiac output with increased peripheral resistance. Pathological observation demonstrated massive infarction of approximately 25% of the surface area of the whole LV. Therefore, the procedure of placing a tube in the LCx artery was shown to be an easy method to produce ischemic HF in pigs.

Selection of the animal HF model should be based on the criteria to be examined as well as its relevance to clinical experience [3,4]. Factors such as available skills, equipment and funding should also be considered. In recent years, one of the most widely used HF models was tachycardia-induced cardiomyopathy [13]. The frequent use of tachycardia-induced cardiomyopathy reflects its advantage, which includes non-invasive preparation, reliable outcome of low cardiac output and biventricular HF with neurohumoral activation, and many published findings of this model [3,4,13]. However, since tachycardia is not the major cause of HF in humans, the exact mechanism for ventricular dysfunction might be different in human patients. Tachycardia-induced ventricular dysfunction, indeed, returns toward normal by termination of the pacing [14,15]. Moreover, the effect of therapeutic agents to modulate heart rate cannot be evaluated in this model.

The other widely used HF models are ischemic models. Ischemic HF is a common cause in humans and this model shows subsequent ventricular remodeling and dysfunction as observed in human patients. Ischemic HF models have been produced in different ways: direct ligation of the coronary artery [5,16–18]; gel, beads or coil embolization into the coronary artery [19–23]; balloon occlusion of the coronary artery [24,25]; and so forth. However, the problem of ligating the coronary artery or other acute procedures is controlling the actual area of myocardial infarction. It may be difficult to produce an appropriate size of myocardial infarction by means of an acute onetime procedure. Thereby, rat models are frequently used, because rats are inexpensive and require less skills and equipment compared with large animals [26,27]. For the purpose of examining the effect of therapeutic interventions on survival, rats are very suitable. However, rat's models have disadvantages including the difficulties in performing hemodynamic measurements and in repetitive blood sampling. The rat HF model due to myocardial infarction also needs thoracotomy and has the same problem in controlling the infarct area as in large animals [27,28]. Each species has an advantage and may be chosen according to the aim to be investigated. However, over the past decade, pigs have been increasingly used in studies of chronic ischemia because of their numerous similarities to humans, including minimal preexisting coronary collaterals as well as similar coronary anatomy and physiology. Therefore, the pig may be an appropriate model for humans [29].

We produced a massive myocardial infarction in pigs by placing a tube in the LCx artery. This procedure needs fluoroscopy, but does not need thoracotomy or an additional procedure and is a relatively easy procedure. The position of the tube in the LCx artery was determined based on previous findings in dogs [6] and preliminary findings in pigs. When we previously used the placement of the tube in the LCx artery in dogs, we intended not to induce myocardial infarction but to induce myocardial hibernation. By placing the tube in the proximal LCx artery and limiting the period of the placement to one week, it was possible to induce in dogs a persistent decrease in wall motion, which was associated with decreased subendocardial blood and was restored to normal by extracting the tube. In the present study, we extended this technique to induce myocardial infarction. We deliberately placed the tube for its distal end to be positioned at about the distal two thirds of the main stream of the LCx artery. Although the mortality rate of the present MI pigs was 40%, the mortality especially within 24 h becomes greater when the tube is placed more distally. Accordingly, the procedure of placing a tube in the coronary artery is easily reversible and is very useful to manipulate coronary circulation by modulating the site and the size of the tube placed for the purpose to be investigated.

Despite deliberate placement of the tube, the infarct size was variable. Since there is variation in the coronary anatomy of individual pigs, these results appeared to be inevitable. As for the effect of the area of myocardial infarction on hemodynamics, an earlier study showed that when more than 40% of the mass of the left ventricle undergoes infarction, cardiogenic shock supervenes in patients [30]. However, infarctions that involve less than 20% of the LCx area usually do not produce major hemodynamic abnormalities [31]. In the present study, pathological observation demonstrated massive infarction, ranging from 20 to 33% of the surface area of the whole left ventricle, associated with left ventricular remodeling and dysfunction, increased left ventricular filling pressure, and low cardiac output with increased peripheral resistance. This moderate degree of LV impairment may be useful, because there is criticism of the coronary ligation model in rats and mice where the infarcts are large and there is so much damaged that so-called ‘cell-based therapy’ may not work. Our model is thought to be representative of patients with mild to moderate LV dysfunction.

In conclusion, the procedure of placing a nylon tube in the LCx artery does not need thoracotomy or an additional procedure and enables production of ischemic HF in pigs. This porcine model of ischemic HF is easily reproducible and may contribute to describing the disease processes and to developing therapeutic interventions in HF.


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

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