Pericardial fat pad removal as a new strategy to treat heart failure in type 2 diabetes.

Background:
Type 2 diabetes (T2D) is an ever-increasing global epidemic. In Australia, T2D is the fastest growing chronic disease affecting more than 1.5 million people. More than 60% of these have cardiovascular disease. Diabetes-induced heart failure, commonly termed diabetic cardiomyopathy, is the major cause of death in diabetic patients and there is currently no specific treatment for it. Diabetic cardiomyopathy is characterised by cardiac fibrosis, hypertrophy and inflammation, diastolic dysfunction, generation of cardiac reactive oxygen species, and cardiac lipotoxicity. These features impair the heart’s ability to relax after each contraction, ultimately leading to heart failure.

In T2D patients and animal models of diabetes, there is an increase in pericardial fat mass which has been proposed to contribute to cardiac disease. Pericardial adipose tissue is the layer of fat that surrounds the heart and constitutes 20-50% of total heart weight. It has historically been regarded as an inert fat layer that, at most, may provide mechanical protection to the coronary arteries. More recently however, the benign nature of this fatty tissue is being re-evaluated. There is growing evidence to support an important role for pericardial fat in the pathophysiology of cardiovascular disease. Clinical studies have shown associations of pericardial fat with cardiovascular disease, atherosclerosis and diabetes. Studies also show that pericardial fat is a source of detrimental inflammatory mediators and adipokines, which due to the fat’s close proximity to the heart wall, may cross into the cardiac muscle and cause cardiac dysfunction.
In this proposal, we will surgically remove the pericardial fat depot from diabetic mice. By removing this direct contact of the fat with the heart wall we may limit infiltration of inflammatory markers and adipokines, therefore improving diastolic dysfunction and ameliorating diabetic cardiomyopathy.

Project aim:
The aim of this Honours project is to investigate whether surgical removal of pericardial fat from the hearts of diabetic mice may improve cardiac function and be used as a potential treatment for diabetic cardiomyopathy.

Techniques:
The animal work will be completed prior to the Honours year, this project will utilise the tissues from the animals. This project will involve RNA and protein extraction from pericardial fat and myocardium from non-diabetic and diabetic mice, for subsequent analyses. This will be followed by RTPCR, western blotting, lipidomics and measurement of adipokines to investigate whether pericardial fat removal counteracts the detrimental impact of diabetes on the heart, by examining changes in expression of the specific genes and proteins responsible for the structural and functional impairments implicated in diabetic cardiomyopathy. The student will also use histological techniques to visualize impact on cardiac morphology (including lipid deposition, fibrosis, ROS dysregulation) and the structure of the pericardial fat.