A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure

Summary

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.

Abstract

In response to an injury, such as myocardial infarction, prolonged hypertension or a cardiotoxic agent, the heart initially adapts through the activation of signal transduction pathways, to counteract, in the short-term, for the cardiac myocyte loss and or the increase in wall stress. However, prolonged activation of these pathways becomes detrimental leading to the initiation and propagation of cardiac remodeling leading to changes in left ventricular geometry and increases in left ventricular volumes; a phenotype seen in patients with systolic heart failure (HF). Here, we describe the creation of a rat model of pressure overload induced moderate remodeling and early systolic dysfunction (MOD) by ascending aortic banding (AAB) via a vascular clip with an internal area of 2 mm². The surgery is performed in 200 g Sprague-Dawley rats. The MOD HF phenotype develops at 8-12 weeks after AAB and is characterized noninvasively by means of echocardiography. Previous work suggests the activation of signal transduction pathways and altered gene expression and post-translational modification of proteins in the MOD HF phenotype that mimic those seen in human systolic HF; therefore, making the MOD HF phenotype a suitable model for translational research to identify and test potential therapeutic anti-remodeling targets in HF. The advantages of the MOD HF phenotype compared to the overt systolic HF phenotype is that it allows for the identification of molecular targets involved in the early remodeling process and the early application of therapeutic interventions. The limitation of the MOD HF phenotype is that it may not mimic the spectrum of diseases leading to systolic HF in human. Moreover, it is a challenging phenotype to create, as the AAB surgery is associated with high mortality and failure rates with only 20% of operated rats developing the desired HF phenotype.

Introduction

Heart failure (HF) is a prevalent disease and is associated with high morbidity and mortality¹. Rodent pressure-overload (PO) models of HF, produced by ascending or transverse aortic banding, are commonly used to explore molecular mechanisms leading to HF and to test potential novel therapeutic targets in HF. They also mimic changes seen in human HF secondary to prolonged systemic hypertension or severe aortic stenosis. Following PO, the left ventricular (LV) wall gradually increases in thickness, a process known as concentric LV hypertrophy (LVH), to compensate and adapt for the increase in LV wall stress. However, this is associated with the ....

Protocol

All methods and procedures described here have been approved by the Institutional Animal Care and Use Committee (IACUC) of Tulane University School of Medicine.

1. Tools and instruments for AAB model creation

1. Obtain disinfectants, such as 70% isopropyl alcohol and povidone-iodine.
2. Obtain ketamine and xylazine for anesthesia and buprenorphine for analgesia.
3. Obtain a heating pad and heavy absorbency disposable underpad with the dimensions of 18 inches x 30 inches........

Discussion

Following PO related to AAB in rat, the LV undergoes concentric remodeling by increasing LV wall thickness, known as concentric LVH, as a compensatory mechanism to counteract for the increase in LV wall stress. Increase in LV wall thickness becomes noticeable during the first week following AAB and reaches its maximum thickness at 2-3 weeks post-AAB. During this time period, activation of maladaptive signal transduction pathways lead to progressive enlargement of the LV with increases in LV volumes, a process known as ec.......

Materials

Name	Company	Catalog Number	Comments
Adson forceps	F.S.T.	11019-12	surgical tool
Alm chest retractor with blunt teeth	ROBOZ	RS-6510	surgical tool
Graefe forceps, curved	F.S.T.	11152-10	surgical tool
Halsted-Mosquito Hemostats, straight	F.S.T.	13010-12	surgical tool
Hardened fine iris scissors, straight	Fine Science Tools F.S.T.	14090-11	surgical tool
hemoclip traditional-stainless steel ligating clips	Weck	523435	surgical tool
Mayo-Hegar needle holder	F.S.T.	12004-18	surgical tool
mechanical ventilator	CWE inc	SAR-830/AP	mechanical ventilator for small animals
Weck stainless steel Hemoclip ligation	Weck	533140	surgical tool