Journal of Pharmacological and Toxicological Methods
Original articleClosed-chest experimental porcine model of acute myocardial infarction–reperfusion
Introduction
The exponential increase in research in regenerative medicine, particularly in cardiology, implies a rapid throughput of advances obtained in basic research, and then applied to the clinical field. To demonstrate efficacy and safety of a specific treatment there is a need for animal models. For economic reasons and because of the availability of natural mutants or mutant strains produced in the laboratory, considerable basic and applied cardiovascular experimentation has been performed in mice and rats; on the assumption that the results can be extrapolated to humans. This is the current status of clinical studies, for example, that assess the effect of stem cell transplantation post-infarction. Although this may be conceptually acceptable with respect to basic cellular biology, myocardium regeneration in a mouse heart with a muscle mass < 100 mg as opposed to about 500 g in the human heart presents problems of magnitude and architectural complexity. As such, it is not feasible to extrapolate the results obtained in rodents to what may occur in humans. The procedures need to be studied in animal models whose characteristics are similar to the organ to be treated. In cardiology, and particularly in the field of ischemic heart disease, the porcine model has been demonstrated to the most effective because of the anatomic, physiologic and pathologic similarities that the pig heart has to the human.
The literature contains descriptions of several models of myocardial infarction in the pig, with or without subsequent reperfusion. The majority of these employ surgical techniques of coronary occlusion following thoracotomy (Cerra et al., 1973, Fozzard, 1975, Hoffmann et al., 2004, Litvak et al., 1957) while, in some cases, less invasive techniques have been used (Eldar et al., 1994, Kraitchman et al., 2000, Krombach et al., 2005, Naslund et al., 1992, Reffelmann et al., 2004, Rochitte et al., 2000, Turschner et al., 2004, Wiggers et al., 1997, Yoshimizu et al., 1986). The endovascular and minimal invasion techniques offer a series of advantages over the surgical technique such as a lower incidence of infections and of related complications which can compromise the survival of the animal and the validity of the results (Edwards et al., 2002, Kraitchman et al., 2000).
The objective of the present study was to assess the viability and reproducibility of an endovascular porcine model of myocardial infarction and reperfusion. We present our preliminary experience using a macroscopic quantitative analysis together with histopathology of the areas of induced infarction.
Section snippets
Study animals
We used a group of 15 domestic pigs of the Large White race. With the exception of three males that had died prematurely, the study was conducted with females. The animals were selected form our experimental-animal farm. They were 2 months old with a mean weight of 25 ± 3 kg. All the investigation procedures and animal care were performed in accordance with the Spanish government's general directives for the protection of experimental animals (Directive 86/609/CE, R.D. 223/1988) and under the
Results
Of the 15 animals employed in the study, 5 died before the end of the intended follow-up period i.e. overall survival of 67%. Three of these premature deaths (animals #13, #14 and #15, the only males in the study) died within 24 h and had evidence of cardiogenic shock and cardiac insufficiency. The necropsy showed ascites as well as pleural and pericardial effusion. Another animal (#10, female) died within the first day post-procedure and was the only animal in which adequate flow was not
Discussion
Having animal models available for the investigation of new routes of therapeutic action on myocardial necrosis is progressively more relevant since, in evaluating the potential effectiveness of new regenerative therapies in humans, the model needs to be characterized not only with respect to the purely biological aspects of the treatment (obtainable from rodents) but also the capacity for regeneration of the architecture of the myocardium; data only obtainable from animals with a heart size,
Conclusion
The endovascular technique that we present of myocardial infarct provocation and subsequent reperfusion in the porcine model is feasible and produces reproducible myocardium damage. This model offers one of the better opportunities for evaluating the different techniques of myocardial regeneration in pre-clinical studies prior to progressing to phase I clinical trials.
References (31)
- et al.
Early phase acute myocardial infarct size quantification: Validation of the triphenyl tetrazolium chloride tissue enzyme staining technique
American Heart Journal
(1981) - et al.
Macroscopic enzyme-mapping verification of large, homogeneous, experimental myocardial infarcts of predictable size and location in dogs
Journal of Thoracic and Cardiovascular Surgery
(1975) - et al.
The experimental production of coronary artery insufficiency and occlusion
American Heart Journal
(1957) - et al.
Time course of fibrillation and defibrillation thresholds after an intravenous bolus of amiodarone—An experimental study
Resuscitation
(2004) - et al.
Ischemia and reperfusion of the porcine myocardium: Effect on collagen
Journal of Molecular and Cellular Cardiology
(1997) - et al.
Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold
Journal of the American College of Cardiology
(1998) - et al.
Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction
Proceedings of the National Academy of Sciences of the United States of America
(2005) - et al.
Sex differences in the structure of the normal porcine myocardial wall
Berliner und Münchener Tierärztliche Wochenschrift
(1994) - et al.
Anesthetic-induced preconditioning: Previous administration of isoflurane decreases myocardial infarct size in rabbits
Anesthesiology
(1997) - et al.
Reversible myocardial ischemia: A chronic model
Review of Surgery
(1973)