inducing hyperlipidemia to characterize diastolic dysfunction in hfpef mice

Investigating HFpEF Pathophysiology in a Hyperlipidemia&amp;#45;Induced Mouse Model

Heart failure with preserved ejection fraction (HFpEF) denotes a cardiometabolic syndrome accompanied by multiple comorbidities and constitutes over 50% of all heart failure cases1,2. Moreover, the frequency of HFpEF has steadily risen over the past decade3. With limited treatment options, HFpEF represents the most significant unmet medical necessity in cardiovascular disease, given its multifaceted pathophysiology4. Thus, an urgent need exists to enhance comprehension of the underlying mechanisms and pathophysiology of HFpEF to develop effective therapies.
Despite significant advancements in recent years, the pathophysiology of HFpEF attributed to lipotoxicity remains incompletely understood. It is established that patients with HFpEF exhibit notable myocardial lipid accumulation compared to those with heart failure with reduced ejection fraction (HFrEF) and healthy controls5. RNA sequencing data from cardiac biopsies showed downregulation of the lipoprotein lipase (LPL) gene in the HFpEF group compared to the healthy and HFrEF patients6. Poloxamer-407 (P-407) is a block co-polymer that induces hyperlipidemia by blocking LPL and subsequently increasing plasma triglycerides and low-density lipoprotein (LDL) cholesterol7. Previous studies demonstrated high LDL-Receptor (LDLR) expression in the hearts of HFpEF mice8. 
Building upon these findings and recognizing the pressing need for animal models accurately mimicking cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed and presented. This model was tailored to explore HFpEF, explicitly focusing on the involvement of lipotoxicity alongside metabolic syndrome. Induced by hyperlipidemia/LPL blockade and enhanced cardiac LDLR expression, this model was established in WT-129 mice on 129J background through biweekly intraperitoneal (i.p.) injections of P-407 combined with a single intravenous (i.v.) injection of adeno-associated virus 9-cardiac troponin T-LDLR (AAV9-cTnT-LDLR)9.
Between 4 and 8 weeks post-treatment, an extensive array of assessments was conducted, encompassing echocardiography, blood pressure recordings, whole-body plethysmography (WBP), continuous electrocardiography (ECG) telemetry, activity wheel monitoring (AWM), as well as biochemical and histological analyses9. At four weeks, the LDLR/P407 or "double treatment" mice exhibited distinct HFpEF features, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness9. Additionally, ECG telemetry and AWM revealed heart blocks and reduced activity, respectively. Notably, blood pressure and renal function remained normal9. By eight weeks, diastolic function deteriorated, and WBP measurements unveiled reduced respiratory rates9. 
Further exploration of the double treatment model revealed fibrosis, elevated wet/dry lung ratios, and heart weight/body weight ratios9. Necropsy revealed ascites, cardiac ischemia, and xanthelasmas. Intriguingly, sudden deaths were documented between 6 and 12 weeks post-treatment9. This murine hyperlipidemia-driven HFpEF model provides a rapid, valuable, and promising experimental tool for unraveling the complexities of metabolic syndrome contributing to diastolic dysfunction with lipotoxicity-mediated HFpEF.

Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF 

A Murine Model of Hyperlipidemia&#45;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 murine model. Despite the rising prevalence and limited treatment options for HFpEF, its 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 underscore 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 provides 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.

Inducing Hyperlipidemia to Characterize Diastolic Dysfunction in HFpEF Mice

inducing-hyperlipidemia-to-characterize-diastolic-dysfunction-hfpef

Research

JoVE Journal

Medicine

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