Optimizing the discovery and assessment of therapeutic targets in heart failure with preserved ejection fraction

Abstract

There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell-derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three-dimensional 'organoids' incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter-relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra-thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.

Inflamed adipose tissue: A culprit underlying obesity and heart failure with preserved ejection fraction

“…Obese mouse models lacking the leptin gene (ob/ob) and leptin receptor (db/db) show signs of HFpEF, including concentric hypertrophy, exercise intolerance, and pulmonary hypertension ( 173 ). Obesity is characterized by leptin resistance in humans; however, the mouse model relies on leptin deficiency and does not accurately recapitulate the clinical obese HFpEF phenotype ( 174 , 175 ). Similarly, the obese ZSF1 (Zucker fatty spontaneously hypertensive heart failure F1 hybrid) rat, which was developed by crossing rat strains with two separate leptin receptor mutations, also exhibited signs of HFpEF (elevated LVEDP, elevated E/e, and preserved LVEF) ( 163 , 176 ).…”

“…Therefore, there is an urgent need for large-animal HFpEF models that can recapitulate the complex features of obese HFpEF in humans. The currently available methods for generating large animal models of HFpEF are summarized in detail elsewhere ( 174 , 175 ). A recent study proposed an HFpEF model in Göttingen minipigs, which induced hypertension and obesity through mineralocorticoid excess and high cholesterol, fat, fructose, and salt diet ( 172 ).…”

Arrhythmic Sudden Cardiac Death in Heart Failure With Preserved Ejection Fraction: Mechanisms, Genetics, and Future Directions

“…Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) may be one option. 120 , 121 Through development of in vitro cardiomyocyte models directly from individual patients, iPSC-CM technology allows for the mechanistic investigation of disease processes unique to an individual’s genetic background. This process may identify new candidate targets for drug therapies.…”

Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

“…When considering CMs, reliable human primary cultures are even more difficult to obtain [30]. First, it is challenging to access adequate quantities of pre-mortem ventricular myocardial tissue.…”

“…First, it is challenging to access adequate quantities of pre-mortem ventricular myocardial tissue. Then, isolated CMs are terminally differentiated and hold a limited life span, and they quickly undergo morphological and structural remodeling with a loss of potential disease hallmarks [30].…”