Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

Keywords: HFpEF; animal models; diabetes; hypertension; metabolic inflexibility; obesity.

Fig. 1. Risk factors, species of choice, and key hallmarks of preclinical HFpEF models.

Hypertension, insulin resistance, obesity and aging are common risk factors for the onset and progression of HFpEF. Preclinical models of HFpEF typically utilize inbred strains, pharmacological, dietary or surgical approaches in rodents, cats, dogs and large animals. HFpEF models have increasingly progressed from signal-factorial toward multi-factorial by combining two or three risk factors in animals. The key integrative signs of HFpEF include morphological abnormalities, hemodynamic changes, pulmonary congestion and exercise intolerance.

Fig. 2. A systematic overview of glucose, fatty acids and ketone body metabolism in the HFpEF heart.

The heart produces energy from various substrates, including glucose, fatty acids, lactate and ketone bodies. Most of the fuel molecules are transported across the inner mitochondrial membrane and subsequently converted to the crucial intermediate acetyl-CoA for further oxidation by the TCA cycle. The energy released synthesizes ATP through the electron transport chain (ETC). The HFpEF heart undergoes “metabolic inflexibility” when facing risk factors. The uncoupling of glycolysis and glucose oxidation, as well as the mismatch between FA uptake and oxidation, eventually result in the accumulation of toxic intermediates and a loss in energy production efficiency. Although ketone consumption helps to ease the HFpEF heart’s production capacity problem, its contribution is minimal and unable to tackle the intracellular environment disorder caused by metabolic inflexibility. CPT-1 Carnitine palmitoyl transferase-1, FA Fatty acids, FATP Fatty acid transport protein, FC Free carnitine, MCT Monocarboxylate transporter-1, MPC Mitochondrial pyruvate carrier, TG Triglycerides, β-OHB β-hydroxybutyrate.

Fig. 3. Therapeutic approaches targeting metabolic derangement in HFpEF.

Different aspects of substrate utilization can be approached to improve metabolic inflexibility. The therapeutic strategies include clinical drugs, traditional Chinese medicine, supplement strategies, and small molecule compounds. Note: SGLT2 inhibitors are approved for treating HFpEF clinically.