Historical perspective
One of the most informative early animal models of heart failure was
developed in rats in which the left coronary artery undergoes surgical
ligation, leading to myocardial infarction, ventricular remodeling, and
systolic failure. This animal model was exploited by Pfeffer et al. in
1979 to explore the correlation between cardiac infarct size and
myocardial dysfunction 24 . These studies led to
the development of novel therapies using angiotensin converting enzyme
inhibitors to prevent adverse ventricular remodeling, and had a major
impact on heart failure therapy and saved many lives22-25 . Yet while this experimental MI model is
an informative approach to investigate mechanisms of cardiac dysfunction
and remodeling, a substantial fraction of the experimental animals may
die from arrhythmia or cardiac rupture following coronary ligation, and
the cardiac remodeling response in the surviving animals is variable and
not consistent. Moreover, each animal requires an individual surgical
intervention, which undermines even medium-throughput screening
approaches. Another commonly used model of heart failure is the
pressure-overload model, which can be used in either mice or rats. In
this model, a ligature is tightened around the animal’s aorta, which
leads first to left ventricular hypertrophy, followed by ventricular
dilation and cardiac dysfunction. This model does mimic aspects of the
heart failure progression observed in human patients26 , but even subtle differences in surgical
techniques and between mouse strains can lead to different outcomes.
With the growing incidence of cardiovascular diseases observed in
patients with diabetes and obesity/metabolic syndrome, animal models of
heart failure have been developed in which animals are exposed to
specific diets (e.g. high-fat/high-sucrose feeding) in various models of
type II diabetes mellitus. However, the cardiac dysfunction that is
induced by these metabolic derangements may develop only after many
months of treatment, and even then may often lead only to a subtle
cardiac phenotype 8 . There are also many
“knockout” mouse models in which individual genes that cause
cardiomyopathy in humans have been targeted; these models have been
quite informative, but the relevance of some of these monogenic
cardiomyopathies to most forms of human heart failure is less clear2 . A recent report 31described a “two hit” approach in mice involving both a dietary
treatment (high fat feeding) along with a pharmacological intervention
(nitric oxide synthase inhibition) that led to the development of a
novel heart failure phenotype. Each of the animal models of heart
failure has its strengths and weaknesses, and of course no model system
can faithfully recapitulate the complex pathways and protean
manifestations of heart failure in humans. There remains an urgent need
for new and more tractable heart failure models that recapitulate key
features of human heart failure.