CoChat
Sign Up
Cited by 484Cardiac electrophysiology and arrhythmiasAnimal testing and alternativesCardiovascular Function and Risk Factors

The DOI matches its Crossref record; 224 of the 224 references it cites were found in a registry or an index; none of the 199 sources its claims cite is checked for support yet.

Small and large animal models in cardiac contraction research: Advantages and disadvantages

Open access
Milani-Nejad, Nima, Janssen, Paul M.L.·2014·Pharmacology & Therapeutics
DOI 10.1016/j.pharmthera.2013.10.007PMC PMC3947198
Open this paper in CoChat — free account

Abstract

The mammalian heart is responsible for not only pumping blood throughout the body but also adjusting this pumping activity quickly depending upon sudden changes in the metabolic demands of the body. For the most part, the human heart is capable of performing its duties without complications; however, throughout many decades of use, at some point this system encounters problems. Research into the heart's activities during healthy states and during adverse impacts that occur in disease states is necessary in order to strategize novel treatment options to ultimately prolong and improve patients' lives. Animal models are an important aspect of cardiac research where a variety of cardiac processes and therapeutic targets can be studied. However, there are differences between the heart of a human being and an animal and depending on the specific animal, these differences can become more pronounced and in certain cases limiting. There is no ideal animal model available for cardiac research, the use of each animal model is accompanied with its own set of advantages and disadvantages. In this review, we will discuss these advantages and disadvantages of commonly used laboratory animals including mouse, rat, rabbit, canine, swine, and sheep. Since the goal of cardiac research is to enhance our understanding of human health and disease and help improve clinical outcomes, we will also discuss the role of human cardiac tissue in cardiac research. This review will focus on the cardiac ventricular contractile and relaxation kinetics of humans and animal models in order to illustrate these differences.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review compares commonly used laboratory animals for cardiac contraction research and concludes that no single model perfectly mirrors the human heart. Larger species generally resemble human contractile and relaxation kinetics more closely, while small rodents offer speed, cost, and genetic tractability.

Key findings

  • Heart size and body mass relate inversely to heart rate and directly to contractile kinetics: mice can beat up to ~800 bpm, elephants ~35 bpm, and ventricular kinetics are ~2–3× faster in rabbits and ~4–12× faster in mice/rats than in humans; canine, swine, and sheep are closer to human values.
  • Molecular differences are substantial: small rodents predominantly express fast α-MHC (>94–100%), whereas human ventricles are mostly slow β-MHC (>90–95%); rabbit, canine, swine, and sheep predominantly express β-MHC. Titin N2BA:N2B ratios are ~0.4–1.2 in humans, ~0.05–0.25 in mice, ~0.06–0.1 in rats, ~0.6–1 in canines, ~1–1.5 in swine, and ~0.35–0.43 in sheep. SERCA handles ~90–92% of calcium removal in rodents versus ~76% in humans; rabbit ~70–74%, canine ~73%, sheep ~81.5%.
  • Exercise reserve and force-frequency responses differ: humans increase heart rate ~140–170% with exercise, versus ~40–50% in rats, ~30–40% in mice, ~71–112% in rabbits, ~96–136% in canines, and ~128–219% in swine. Human trabeculae force rises ~81–168% from 0.5 to 2.5 Hz; rabbit ~120–200% (1–4 Hz), rat ~30–40% (4–8 Hz), mouse nearly flat (8–12 Hz), and sheep ~139–171% (0.5–2 Hz).
  • Model trade-offs: mice/rats are cheap, fast, and genetically tractable but most distant from human contraction; rabbits are intermediate; canines are closest for electrophysiology, sino-atrial node, Purkinje fibers, and exercise but are costly and harder to approve; swine and sheep are strong large-animal preclinical models with high housing costs; human tissue is valuable but scarce and variable.

Methods

  • Narrative review of published literature comparing mouse, rat, rabbit, canine, swine, sheep, and human myocardium, focused on ventricular contraction and relaxation kinetics.
  • Synthesizes ex vivo isometric trabeculae data and in vivo pressure-volume/catheterization data, plus molecular and calcium-handling comparisons, with tables/figures normalizing parameters to human values.
  • No primary experiments or systematic search/meta-analysis are described.

Limitations

  • The paper states that no ideal animal model exists; each has advantages and disadvantages, and translation depends on the process studied and on how well the disease model recapitulates human disease progression (e.g., sudden aortic banding versus gradual human aortic stenosis).
  • Human samples are limited and variable because of genetics, medications, diet, exercise, social habits, and disease severity; donor hearts often have underlying abnormalities, and ischemia, delayed freezing, LVAD-induced remodeling, and inotropic agents can confound results.
  • Evident from the text: the review is narrative rather than systematic, and cross-species comparisons draw on heterogeneous studies with differing temperatures, stimulation frequencies, anesthesia, and sample sources, which can affect contractile measurements.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.pharmthera.2013.10.007

Cites

224 of 224 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 199 cited sources checked · 0 supported · 0 flagged

Show all 139 claims

  • Probably not a substantial claim. 21
  • It may state two separate claims as one. 67
82 of 82

  • The paper relies on this without support.

    The basic principles of cardiac excitation and contraction are relatively conserved across the species discussed.

    “The basic principles of cardiac excitation and contraction in all of the species discussed in this review are relatively conserved.”

  • The paper relies on this without support.

    The cardiovascular system of each animal evolved differently to meet the demands of that species.

    “the cardiovascular system of each animal has evolved differently in order to meet the demands of that species.”

  • The paper relies on this without support.

    Small rodents are easier to handle and house, have shorter gestation, and lower maintenance cost than larger animal models.

    “Small rodents are easier to handle and house, have a shorter gestation time, and have lower maintenance cost than larger animal models.”

  • The paper relies on this without support.

    Cardiac excitation, contraction, and relaxation of small rodents and humans share many similarities, and both express proteins with similar functions and roles.

    “Cardiac excitation, contraction, and relaxation of small rodents and humans share many similarities and both groups express proteins with similar functions and roles.”

  • The paper relies on this without support.

    The closer the heart or body weight of an animal model is to human, the more similar its heart is to human.

    “As a simple rule, the closer the heart or body weight of the animal model to human; the more similar are the hearts.”

  • The paper relies on this without support.

    Human cardiac tissue samples are available in limited quantities and exhibit great variability.

    “These samples are however available in very limited quantities, and exhibit great variability due to differences in factors such as genetics, medications, diets, social habits, and diseases.”

  • The paper relies on this without support.

    There is a need for a suitable animal model where cardiovascular physiology and disease can be studied efficiently and reliably with potential translational applicability to humans.

    “There thus exists a need to have a suitable animal model where cardiovascular physiology and disease can be studied efficiently and reliably with potential translational applicability to humans.”

  • The paper relies on this without support.

    A mouse typically can increase cardiac output by no more than one-third, while highly trained humans can increase it up to 10-fold.

    “Where a mouse can increase its cardiac output by typically no more than one-third, humans can increase cardiac output as high as 10-fold in highly trained individuals.”

  • The paper relies on this without support.

    Rabbits cost less to acquire and house than larger animal models such as canine and sheep.

    “the cost of acquiring and housing rabbits is still significantly much lower which makes them an attractive alternative to larger animal models in cardiac research from an economic/logistic perspective.”

  • The paper relies on this without support.

    Rabbits cost more to acquire and house than mice and rats.

    “One of the major disadvantages of using rabbits is the cost associated with acquiring and housing them as compared to mice and rats.”

  • The paper relies on this without support.

    Rabbits are cheaper than larger animal models including canine, pig, and sheep.

    “rabbits are still cheaper than larger animal models including canine, pig, and sheep.”

  • The paper relies on this without support.

    Human population heterogeneity is not reflected in inbred laboratory mouse, rat, or rabbit strains.

    “the human population is heterogeneous with slight genetic variations; a property which is not reflected in the inbred laboratory mouse, rat, or rabbit strains.”

  • The paper relies on this without support.

    Housing and maintenance of canine models is considerably more expensive than small rodents and rabbits.

    “The housing and maintenance of canine models is considerably more expensive than small rodents and rabbits”

  • The paper relies on this without support.

    Obtaining necessary approval for performing experiments in canines is generally difficult.

    “it is generally difficult to obtain such approval for using canines as an animal model.”

  • The paper relies on this without support.

    Even if canine use is justified and approval obtained, the number of animals that can be used can be limited.

    “even if the use of canines is justified and the appropriate approval is obtained, the number of animals that can be used can be limited.”

  • The paper relies on this without support.

    Swine have relatively high cost of housing and maintenance.

    “Swine, typical of large animal models, have a relatively high cost of associated with housing and maintenance.”

  • The paper relies on this without support.

    The time and cost associated with development of genetic swine models is a disadvantage compared with genetic mice models, which can be developed more rapidly and with lower cost.

    “The time and cost associated with development of genetic swine models is a disadvantage when compared to genetic mice models which can be developed more rapidly and with lower cost.”

  • The paper relies on this without support.

    Canines are highly similar to humans in the sino-atrial node and Purkinje fibers.

    “For example, if the focus of the study is on sino-atrial node or purkinje fibers, it is recommended that canines be used due to the high degree of similarity that they share in these aspects with humans.”

  • The paper relies on this without support.

    Approval for experiments on canines is often harder to obtain.

    “due to the often greater difficulty associated with obtaining approval for performing experiments on canines.”

  • The paper relies on this without support.

    The hearts of larger species and humans are inherently different.

    “Nonetheless, even the hearts of these larger species and humans are inherently different.”

  • The paper relies on this without support.

    Human myocardium for ex vivo analysis usually comes from rejected donor hearts or end-stage failing hearts donated after transplantation.

    “Human myocardium suitable for ex vivo analysis can be typically obtained from 1) rejected donor hearts that were not suitable for cardiac transplantation or 2) end-stage failing hearts that were donated after the patient received cardiac transplantation.”

  • The paper relies on this without support.

    Heart failure patients eligible for transplantation undergo tests and appointments that record information such as ejection fraction and medication compliance.

    “Typically, heart failure patients who are eligible for transplantation undergo a battery of tests and regular physician appointments where information ranging from ejection fraction to medication compliance is recorded.”

  • The paper relies on this without support.

    Most donor hearts have anatomical or acquired abnormalities that excluded them from transplantation.

    “In most cases, such donor hearts have some underlying anatomical and/or acquired abnormalities (such as coronary artery disease, low ejection fraction, and/or advanced age) that excluded them for cardiac transplantation.”

  • The paper relies on this without support.

    In some cases, inotropic agents are used to maintain organ perfusion during procurement.

    “Furthermore, in some cases inotropic agents are used in order to maintain proper organ perfusion during the organ procurement process”

  • The paper relies on this without support.

    Inotropic agents can alter post-translational modifications of cardiomyocyte proteins or, with extended use, protein expression levels.

    “and the use of such agents can cause alterations in post-translational modifications of cardiomyocyte proteins, or when given for extended periods of time, modify protein expression levels.”

  • The paper relies on this without support.

    Documentation of inotropic agent use is often unavailable to researchers or omitted at publication.

    “Unfortunately, documentation of the use of such agents is not always readily available to researchers, and/or omitted at the time of publication.”

  • The paper relies on this without support.

    Ischemia can occur during excision of the heart from the thoracic cavity in both rejected donor and end-stage failing hearts.

    “One concern, common to both rejected donor and end-stage failing hearts, is that ischemia can happen during excision of the heart from the thoracic cavity.”

  • The paper relies on this without support.

    Ischemia can affect myocardial tissue.

    “Such ischemia can affect the myocardial tissue”

  • The paper relies on this without support.

    Animal heart samples can be flash frozen quickly, sometimes within seconds.

    “Heart samples from animal models can be quickly (if necessary within seconds) be flash frozen.”

  • The paper relies on this without support.

    Quick freezing is usually impractical for donated human hearts, and freezing or placing on ice may take minutes to hours.

    “However, in most settings such quick freezing is not practical for donated human hearts and in most cases it might take several minutes or even hours to freeze tissues or at least place on ice.”

  • The paper relies on this without support.

    Delays in freezing human heart samples will hinder studies of post-translational modifications because such processes can occur and reverse within minutes.

    “Such delays will become problematic if the goal of the study is to determine the post-translational modifications of proteins, as several of these process can occur, and reverse, in minutes.”

  • The paper relies on this without support.

    Human samples are available only in limited quantities.

    “One common limitation of both groups is that these human samples are available in limited quantities.”

  • The paper relies on this without support.

    Pressure-overload in animal models is typically induced suddenly by placing a band on the aorta.

    “Typically, such pressure-overload in animal models is induced suddenly with placing of a band over some part of the aorta.”

  • The paper relies on this without support.

    Aortic constriction is used to induce hypertrophy and heart failure in small and large animal models.

    “For example, consider aortic constriction that is used to induce hypertrophy and heart failure in both small and large animal models.”
34 of 34

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Flagged first, then by citations

Show all 224 references

Cited by

Sorted by citations

Items 301–400 of 478

Related

See all

Metadata

Authors
Milani-Nejad, N., & Janssen, P. M. L.
Affiliations
The Ohio State University (US)
Corresponding author
Janssen, Paul M.L.
ORCID
Janssen, Paul M.L.
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2014-03
Volume
141
Issue
3
Pages
235-249
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/j.pharmthera.2013.10.007
PMC
PMC3947198
OpenAlex
W1966140207
Cited by
484
References
224
Citations by year
2026: 37 · 2025: 48 · 2024: 42 · 2023: 51 · 2022: 56 · 2021: 51 · 2020: 53 · 2019: 40 · 2018: 39 · 2017: 22 · 2016: 17 · 2015: 21 · 2014: 7
FWCI
10.20
Type
journal article
Language
en
Open access
Locations
  • Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL113084, RC1HL099538)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
cardiac contraction, species differences, mice, rats, rabbits, canine, pigs, sheep, human cardiac tissue, cardiac hypertrophy
MeSH terms
Animals, Disease Models, Animal, Heart Diseases, Heart Ventricles, Humans, Myocardial Contraction, Species Specificity, Ventricular Function, Models, Animal

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-04, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-04 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review