Modeling heart failure in animal models for novel drug discovery and development

ABSTRACT

Introduction: When investigating drugs that treat heart diseases, it is critical when choosing an animal model for the said model to produce data that is translatable to the human patient population, while keeping in mind the principles of reduction, refinement, and replacement of the animal model in the research.

Areas covered: In this review, the authors focus on mammalian models developed to study the impact of drug treatments on human heart failure. Furthermore, the authors address human patient variability and animal model invariability as well as the considerations that need to be made regarding choice of species. Finally, the authors discuss some of the most common models for the two most prominent human heart failure etiologies; increased load on the heart and myocardial ischemia.

Expert opinion: In the authors’ opinion, the data generated by drug studies is often heavily impacted by the choice of species and the physiologically relevant conditions under which the data are collected. Approaches that use multiple models and are not restricted to small rodents but involve some verification on larger mammals or on human myocardium, are needed to advance drug discovery for the very large patient population that suffers from heart failure.

KEYWORDS:

• Animal model
• human heart failure
• ischemia
• hypertension
• contraction

Article Highlights

• Animal model studies often use inbred strains that do not reflect the variability of the human patient population, limiting generalization of the study outcome to the overall patient population.

• One of the most common pathological signatures of human heart failure is the blunting or reversal of the force-frequency relationship, which is a regulatory mechanism predominantly used by larger species, but not by small species.

• The heart rate of a species is critically related to the underlying molecular composition of ion channels and contractile protein isoforms.

• Human heart failure develops in many etiologies over many years/decades. Models that provide a much faster onset of disease may not necessarily reflect on the human disease process and progression.

• Drug treatment of ex vivo/in vitro human heart myocardium allows for a more direct translation to the patient population, but those investigations are logistically challenging.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

PM Janssen’s lab is funded by National Institutes of Health grants RC1HL099538 and R01HL113084.