Abstract
BackgroundAlthough the incidence of acute death related to coronary artery disease has decreased with the advent of new interventional therapies, myocardial infarction remains one of the leading causes of death in the US. Current animal models developed to replicate this phenomenon have been associated with unacceptably high morbidity and mortality. A new model utilizing the first diagonal branch of the left anterior descending artery (D1-LAD) was developed to provide a clinically relevant lesion, while attempting to minimize the incidence of adverse complications associated with infarct creation.MethodsEight Yucatan miniature pigs underwent percutaneous embolization of the D1-LAD via injection of 90 µm polystyrene micro-spheres. Cardiac structure and function were monitored at baseline, immediately post-operatively, and at 8-weeks post-infarct using transthoracic echocardiography. Post-mortem histopathology and biochemical analyses were performed to evaluate for changes in myocardial structure and extracellular matrix (ECM) composition respectively. Echocardiographic data were evaluated using a repeated measures analysis of variance followed by Tukey’s HSD post hoc test. Biochemical analyses of infarcted to non-infarcted myocardium were compared using analysis of variance.ResultsAll eight pigs successfully underwent echocardiography prior to catheterization. Overall procedural survival rate was 83% (5/6) with one pig excluded due to failure of infarction and another due to deviation from protocol. Ejection fraction significantly decreased from 69.7 ± 7.8% prior to infarction to 50.6 ± 14.7% immediately post-infarction, and progressed to 48.7 ± 8.9% after 8-weeks (p = 0.011). Left ventricular diameter in systole significantly increased from 22.6 ± 3.8 mm pre-operatively to 30.9 ± 5.0 mm at 8 weeks (p = 0.016). Histopathology showed the presence of disorganized fibrosis on hematoxylin and eosin and Picro Sirius red stains. Collagen I and sulfated glycosaminoglycan content were significantly greater in the infarcted region than in normal myocardium (p = 0.007 and p = 0.018, respectively); however, pyridinoline crosslink content per collagen I content in the infarcted region was significantly less than normal myocardium (p = 0.048).ConclusionSystolic dysfunction and changes in ECM composition induced via embolization of the D1-LAD closely mimic those found in individuals with chronic myocardial infarction (MI), and represents a location visible without the need for anesthesia. As a result, this method represents a useful model for studying chronic MI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0547-4) contains supplementary material, which is available to authorized users.
Highlights
The incidence of acute death related to coronary artery disease has decreased with the advent of new interventional therapies, myocardial infarction remains one of the leading causes of death in the US
The aims of the current study were to utilize the location of the first diagonal branch of the left anterior descending (LAD) to create a porcine model of chronic myocardial infarction (MI) that: (1) produces an infarction that models the cellular and molecular changes seen in humans with chronic, trans mural infarcts, (2) produces an infarcted area that can be visualized via standard echocardiography with greater than or equal to 20% reduction in left ventricular ejection fraction (LVEF), and (3) overcomes the adverse complications compared to those reported with previous MI models
Predominant use of the distal LAD as the location of embolism likely contributes to the aforementioned complications, as the LAD supplies a large region of myocardium, including the apex, distal interventricular septum, and a portion of the right ventricle [11, 14]
Summary
The incidence of acute death related to coronary artery disease has decreased with the advent of new interventional therapies, myocardial infarction remains one of the leading causes of death in the US. A new model utilizing the first diagonal branch of the left anterior descending artery (D1-LAD) was developed to provide a clinically relevant lesion, while attempting to minimize the incidence of adverse complications associated with infarct creation. Coronary artery disease and subsequent myocardial infarction (MI) is the leading cause of cardiovascular morbidity and mortality in the United States, accounting for 1 in every 6 deaths [1]. Porcine models have gained popularity due to greater similarity in coronary anatomy and cardiac physiology compared to humans. Porcine models have supplanted other animals in the recreation of the native diseases found in humans due to their closer similarity to human cardiac anatomy and pathophysiology
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