A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction

Our research aims at examining heart failure with preserved ejection fraction known as HFpEF, specifically investigating the effects of lipotoxicity. We seek to elucidate the intricate relationship between metabolic syndrome and lipotoxicity in driving HFpEF progression and uncover the underlying mechanisms driving HFpEF pathophysiology using this experimental mirroring model. Despite the rising prevalence and limited treatment options for HFpEF, it's pathophysiological mechanisms mainly related to metabolic syndrome remain poorly understood.

This model presents a unique opportunity to bridge this gap and potentially develop new therapies for HFpEF. Our model's most important advantage is its ability to mimic significant lipid mishandling observed in HFpEF patients. This mouse model offers valuable insights into the pathophysiology of HFpEF, especially cardiac metabolism.

Our findings under score the importance of fatty acid and cholesterol mishandling in cardiometabolic HFpEF. This model perfectly shows how fatty acid deprivation disrupts metabolism at different levels. It provide researchers with potential avenues to discover novel traps for HFpEF patients.

Here at the Shahada Laboratory, we will focus on translating this model into large animals. We will investigate questions related to the pathogenesis, sudden death and potential therapeutic interventions targeting lipotoxicity, inflammation and cardiac remodeling. Instructor[To Begin, thaw the viral vector stock vials on ice for 20 minutes and dilute the AAV particles in 100 microliters of DPBS.

Load the diluted AAV solution into a one milliliter syringe with a 28 to 30 gauge needle, avoiding air bubbles. Secure the anesthetized mouse in a tail illuminator restrainer, and use a gauze pad to clean the injection site with an antiseptic. Massage the tail with two fingers until the vein is observed.

Then inject the vector into the tail vein at a low angle and withdraw the needle. Using a finger apply pressure immediately to the injected site to stop the bleeding. To prepare Poloxamer 407, dissolve it in DPBS on a rotator overnight at four degrees Celsius in a biosafety cabinet.

Next, restrain the mouse manually under a fume hood positioning its head and body downwards. With an antiseptic, clean the injection site in the left lower quadrant of the abdomen, lateral to the midline. To inject P 407, insert the needle into the peritoneal cavity at an angle of 45 degrees or less.

After four weeks of hyperlipidemia induction, echocardiography revealed heart failure with preserved ejection fraction as intraventricular relaxation time was prolonged. An increased ratio between early mitral lean flow velocity and mitral annular early diastolic velocity, along with a decreased early to late diastolic trans mitral flow velocity was observed.