Medicine
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A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure
Chapters
Summary April 30th, 2020
We describe the creation of a rat model of pressure overload induced moderate remodeling and early systolic dysfunction where signal transduction pathways involved in the initiation of the remodeling process are activated. This animal model will aid in identifying molecular targets for applying early therapeutic anti-remodeling strategies for heart failure.
Transcript
The rat pressure overload induced moderate remodeling and early systolic dysfunction model is a milder version of the previously created rat pressure overload induced for systolic heart failure model. The study I love, study of the pathways involved in the initiation and propagation of cardiac remodeling, especially as it pertains to metabolic remodeling, myocardial dysfunction, and calcium cycling. Before beginning the procedure, adjust a vascular hemoclip ligation tool via precut seven inch piece of plastic to modify the clip to the appropriate internal area, depending on which heart failure model is desired.
Next, confirm a lack of response to fetal reflex in the anesthetized rat and shave the hair under the right axilla at the right lateral thoracic area. Tape the animal's limbs to a plastic dissection board and intubate the animal with a 16-gauge angiocath. Initiate mechanical ventilation with tidal volumes of two milliliters at 50 cycles per minute and a fraction of inspired oxygen of 21 percent.
A symmetrical rise in the chest wall should be observed with each breath. Carefully position the animal onto its left lateral side, and bend the tail in a U-shaped manner. Then gently tape the tail to the plastic board and disinfect the exposed skin with povidone iodine.
Using a scalpel, make one to two centimeter horizontal skin incisions in the right axilla area one centimeter below the right axilla and dissect the thoracic muscular layer until the thoracic rib cage is reached. Make a one centimeter thoracotomy between the second and third rib and place a chest retractor into the incision before gently dissecting the two lobes of the thymus gland. Push the lobes to the side and use a curved gray forceps to carefully blunt dissect the ascending aorta from the superior vena cava.
Once the ascending aorta has been isolated, use the forceps to carefully lift the vessel and place the vascular clip around the ascending aorta. Then use 2-0 monofilament suture to close the thorax before suturing the muscular layer of the chest via A-3-0 vicryl taper suture, and close the skin by a nylon 3-0 monofilament suture. For echocardiographic imaging, after sedation, remove the hair from the anterior chest of the rat and stabilize the animal in the supine position on a plastic dissection board.
Acquire 2D parasternal long-axis and a 2D parasternal short-axis view clips at the level of the papillary muscle. Obtain M-mode images from the short parasternal axis view at the level of the papillary muscle to measure left ventricular septal and posterior wall thickness in diastole and the left ventricular end-diastolic and end-systolic diameters. Acquire 2D M-mode short parasternal axis view images at the level of the mid-papillary muscle to serve as a reference to obtain reliable serial and subsequent left ventricle measurements.
Then obtain M-mode images of the long parasternal axis view at the level of the aortic valve to assess the relative aortic two-left atrium diameter and end-systole. Characterization of the heart failure phenotypes that develop eight to 12 weeks following ascending aortic banding can be easily performed via echocardiography. 2D long parasternal axis and 2D short parasternal axis echocardiography video clips can be used to measure the left ventricle length and area at end-diastole and end-systole in sham and MOD heart failure animals.
In this 2D short parasternal axis view, the increased left ventricle hypertrophy and the MOD phenotype can be observed compared to the appearance of the left ventricle in the sham echocardiography image. Left ventricle and diastolic volume in the MOD heart failure phenotype usually ranges between 600 to 700 microliters with vary few animals exhibiting an end-diastolic volume greater than 700 microliters. The left ventricle and systolic volume in the MOD phenotype ranges between 120 to 160 microliters.
In these representative pressure volume loop tracings of sham week three post-descending aortic banding, MOD and overt systolic heart failure animals, the left ventricle maximum pressure at week eight is increased dramatically in MOD and overt systolic heart failure animals compared to week three post-descending aortic banding animals. due to the mismatch between the growth of the animal and the aorta and the fixed created stenosis in the ascending aorta. In addition, week three post AAB animals are fully compensated at three weeks with a decrease in the left ventricle and diastolic and asystolic volumes compared to sham animals.
Of note, the rat pressure overload induced heart failure model is associated with high mortality and failure rates with only about 20 percent of the rats that undergo ascending aortic banding transitioning to develop the MOD heart failure phenotype. The most important thing to remember is to properly characterize the phenotype of animals by echocardiography so that to narrow the biological variations observed between animals within the same group. In more dynamic assessment using pressure volume loop catheter can be used to assess relaxation, contract dysfunction, and myochardial stiffness.
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