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

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
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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.

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

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Claims the paper makes

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

  • Findingcitation

    Daily housing fees for sheep, pigs, canines, and rabbits are about 80, 60, 90, and 30 times those for mice, based on 2013 Ohio State University ULAR fees and five mice per cage.

    “Just the daily housing fees of sheep, pigs, canines, and rabbits are approximately 80, 60, 90, and 30 times more expensive than mice, respectively (values based upon 2013 fees charged by The Ohio State University ULAR and assuming 5 mice per cage).”
    Quote in the paperSubstantial claim
  • Findingown data

    Sheep cost more to buy and house in animal facilities than small animal models.

    “Most notably, sheep are much more expensive to purchase and maintain in animal facilities than small animal models.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Successful cardiac transduction in large species requires surgical and catheter-based approaches that preferentially target the heart.

    “Successful cardiac transduction in large species requires surgical and catheter-based approaches that can preferentially target the heart”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pepe, et al., 2010 source

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    • cites Pleger, et al., 2011 source

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  • Premisenone given

    A variety of mouse and rat cardiac dysfunction and heart failure models are available, each with advantages and disadvantages.

    “There are a variety of mouse and rat cardiac dysfunction and heart failure models available, each with its own advantages and disadvantages.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Diazoxide affects action potential duration of atria and ventricles differently in mouse and human.

    “diazoxide, an ATP sensitive potassium (KATP) channel opener, affects action potential duration (APD) of atria and ventricles of mouse and humans differently.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fedorov, et al., 2011 source

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    • cites Glukhov, Fedorov, et al., 2010

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    Findingnone given

    At the authors' institution, human hearts are shared among laboratories studying processes from myofilament contraction to tissue-level cardiac excitation.

    “Currently in our institution, human hearts are shared among several laboratories which study processes ranging from contraction at the myofilament level to cardiac excitation at the tissue level.”
    Quote in the paperNot a substantial claim

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    Findingown data

    Left ventricular pressure stays constant, but contractile and relaxation kinetics scale with body weight and approach human values as animal size increases.

    “Note that while left ventricular pressure remains constant, contractile and relaxation kinetics scale with body weight and these kinetics approach those of humans as animal size increases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Figure 2 presents ex vivo and in vivo contractile and relaxation parameters normalized to human values.

    “Figure 2 shows various ex vivo (only mouse, rat, rabbit, canine, and human available) and in vivo (all species) contractile and relaxation parameters normalized to human values.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Human and animal hearts differ, and these differences can be more pronounced or limiting depending on the species.

    “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.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Mouse and rat predominantly express N2B titin and considerably lower N2BA titin, with N2BA:N2B ratios of ~0.05-0.25 in mouse and ~0.06-0.1 in rat.

    “Mouse and rat predominately express N2B titin and considerably lower N2BA titin isoform with N2BA:N2B ratio ranges of ~0.05–0.25 in mouse and ~0.06–0.1 in rat”
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    • cites Cazorla, et al., 2000 source

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    • cites Neagoe, Opitz, Makarenko, & Linke, 2003

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    • cites Opitz & Linke, 2005

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    Premisecitation

    PLB knockout mice have enhanced cardiac contractility without affecting lifespan.

    “The phospholamban (PLB) knock-out mouse has enhanced cardiac contractility, without affecting life span”
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    • cites Slack, et al., 2001 source

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    Interpretationreasoning

    These cases illustrate differential responses of mice and humans to genetic alterations and limitations of genetic mouse models for human cardiovascular disease.

    “These cases illustrate the differential response of mice and humans to genetic alterations and the limitations of genetic mouse models in studying human cardiovascular disease.”
    Quote in the paperSubstantial claim

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    Premisecitation

    At the same concentration, diazoxide decreased mouse atria APD but had no effect on human atria APD; in ventricles, it did not affect mouse ventricle APD but slightly decreased human ventricle APD.

    “the same concentration of diazoxide decreased mouse atria APD while it had no effect on human atria APD. The opposite was observed in the ventricles; diazoxide did not affect mouse ventricle APD while it slightly decreased human ventricle APD”
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    • cites Fedorov, et al., 2011 source

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    • cites Glukhov, Fedorov, et al., 2010

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    Premisecitation

    The mdx mouse model has mild cardiomyopathy, mild limb-skeletal muscle dysfunction, and normal life span, unlike human DMD.

    “The mdx (dystrophin deficient) mouse model has a rather mild cardiomyopathy, mild limb-skeletal muscle dysfunction, and a normal life span, in contrast to human counterparts”
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    Premisecitation

    Mice lacking both dystrophin and utrophin show a much more severe phenotype and reduced lifespan.

    “a mouse model lacking both dystrophin and utrophin shows a much more severe phenotype, and a reduced lifespan”
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    • cites Deconinck, et al., 1997 source

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    • cites Delfin, et al., 2011 source

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    • cites Janssen, Hiranandani, Mays, & Rafael-Fortney, 2005

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    Interpretationreasoning

    The choice of animal model affects experimental outcomes and whether findings can be reasonably translated to humans.

    “Depending on the cardiovascular process being studied, the choice of animal model needs to be considered carefully since it affects experimental outcomes and whether findings of the study can be reasonably translated to humans.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    These studies highlight limitations of directly translating pharmacological efficacy and toxicity from murines to humans, in addition to known differences in pharmacokinetics.

    “These studies highlight the limitations of directly translating pharmacological efficacy and toxicity of compounds from murines to humans, which is in addition to known differences in pharmacokinetics.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Lower doses of monocrotaline result in right ventricular hypertrophy while higher doses are required to induce right-sided heart failure.

    “lower doses of this compound result in right ventricular hypertrophy while higher dosage is required in order to induce right-sided heart failure”
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    • cites Hessel, et al., 2006 source

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    Premiseown data

    Heart rate is inversely related to body weight while blood pressure remains relatively constant across laboratory animals and humans.

    “Table 1 shows the inverse relationship between body weight and heart rate while blood pressure remains relatively constant across various laboratory animals and humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Small rodents are effective animal models with distinct advantages over larger animal models but have various limitations and disadvantages.

    “Small rodents are effective animal models with distinct advantages over larger animal models; however, as will be discussed next in detail, they have various limitations and disadvantages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    No single animal model is ideal for cardiac research; each commonly used model has its own advantages and disadvantages.

    “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.”
    • Also stated in: § 1. Introduction · plain
      “there is no perfect animal model of the human heart; each model has its own set of advantages and disadvantages.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Mouse action potentials have rapid repolarization and lack a prominent plateau phase found in human cardiomyocytes.

    “Mouse action potentials have a rapid repolarization and lack a prominent plateau phase which is found in human cardiomyocytes”
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    • cites Nerbonne, 2004 source

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    Premisecitation

    Mouse models can be developed more quickly and at lower cost than larger species because of their short gestation.

    “mouse models can be developed in a shorter period of time due to their short gestation age of ~18–21 days”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ostergaard, et al., 2010

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    Interpretationnone given

    These heart failure models have lower cost than larger animals and allow investigation of roles of proteins and signaling pathways by combining intervention models with genetically modified mice.

    “The advantages of using these models are that they present significantly lower cost than larger animals, and the ability to investigate roles of various proteins and signaling pathways in progression of heart disease by combining these intervention models and genetically modified mouse models.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Ten weeks of pulmonary artery banding is sufficient to induce right ventricular hypertrophy in rabbits without signs and symptoms of heart failure, and with altered right atrial calcium handling.

    “ten weeks of pulmonary artery banding (PAB) is sufficient to induce hypertrophy in rabbits without signs and symptoms of heart failure in the right ventricle (Varian, et al., 2009) and with altered right atrial calcium handling (Gupta, et al., 2009).”
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    Premisecitation

    Hypothyroidism in rats down-regulates alpha-MHC and up-regulates beta-MHC.

    “hypothyroidism (either by administration of propylthiouracil or thyroidectomy) in rats results in down-regulation of α-MHC and up-regulation of β-MHC (Rundell, et al., 2005; Tang, et al., 2005).”
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    • cites Rundell, et al., 2005 source

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    Premisenone given

    Rabbit cardiac contraction and relaxation kinetics are approximately 2-3 times faster than human, but more similar than smaller rodents whose kinetics are 4-12 times faster.

    “The kinetics of rabbit cardiac contraction and relaxation are approximately 2–3 times faster than humans yet more similar than smaller rodents where kinetics are as much as 4–12 times faster (See Table 2).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Post-rest potentiation behavior of isolated cardiac muscles is species-dependent: rabbits exhibit post-rest decay, while humans and rats show post-rest potentiation.

    “Following periods of rest after steady pacing, rabbits exhibit a post-rest decay where the first twitch tension is decreased while humans and rats show post-rest potentiation where the first twitch tension is increased as the rest periods are prolonged (Janssen, Lehnart, Prestle, & Hasenfuss, 1999; Maier, Bers, et al., 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Janssen, et al., 1999 source

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    Premisecitation

    Various methods are available to generate rabbit heart failure models, including pacing-induced failure, combined aortic insufficiency-induced volume overload and aortic constriction-induced pressure overload, and coronary ligation.

    “Various methods for generating rabbit heart failure models are available including pacing-induced failure (D. Liu, Gao, Roy, Cornish, & Zucker, 2006), combined aortic insufficiency induced volume overload and aortic constriction induced pressure overload (Pogwizd, et al., 1999), and coronary ligation (Maurice, et al., 1999; D. C. White, et al., 2000).”
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    • cites D. Liu, et al., 2006 source

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    • cites Pogwizd, et al., 1999 source

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    • cites Maurice, et al., 1999

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  • May combine two claims.

    Interpretationreasoning

    Mouse and rat hearts share many characteristics but also differ.

    “The hearts of mouse and rat share many characteristics; however, there are differences even between these two species.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    Many aspects of rabbit myocardium are more similar to humans than small rodent myocardium, making rabbits generally more representative of the human heart.

    “Many aspects of rabbit myocardium have greater similarity to humans than small rodents, making rabbits a model generally more closely representative of the human heart.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Rabbit in vivo heart rate range is 155-360 bpm, higher than humans but closer to humans than mouse and rat heart rates.

    “Rabbits have an in vivo heart rate range of 155–360 bpm (Gaustad, Rolim, & Wisloff, 2010; Jover, McGrath, & Ludbrook, 1987) which is still higher than humans (Flamm, et al., 1990; Stratton, et al., 1994) but significantly closer than mouse and rats”
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    • cites Gaustad, et al., 2010 source

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    • cites Jover, et al., 1987 source

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    • cites Flamm, et al., 1990 source

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    Premisecitation

    Increasing stimulation frequency in rabbit in vitro preparations from 1 to 4 Hz and human preparations from 0.5 to 2.5 Hz increases contractile force by about 120-200% and 81-168%, respectively.

    “Increasing the stimulation frequency in rabbit (from 1 Hz to 4 Hz) and human in vitro muscle preparations (from 0.5 Hz to 2.5 Hz) results increase in contractile force of about 120–200% and 81–168%, respectively”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chaudhary, et al., 2004 source

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    • cites Monasky & Janssen, 2009

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    • cites Pieske, et al., 1996 source

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    Premisecitation

    In mouse right ventricular myocardium, phenylephrine has a net negative inotropic effect, whereas in rat it has a net positive inotropic effect.

    “in mice the overall effect of this drug is a net negative inotropic response while in rats it is a net positive inotropic response (McCloskey, et al., 2002).”
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    • cites McCloskey, et al., 2002 source

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    Interpretationreasoning

    Despite closer similarity to humans than mice and rats, differences between rabbit and human myocardium remain and can cause differential effects of a study or therapeutic intervention.

    “Despite a closer similarity to humans than mice/rats, differences between rabbit and human myocardium remain, which can result in a particular study or therapeutic intervention to have differential effects in rabbits and humans.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Rabbit SERCA resequesters calcium faster than human SERCA in isolated myocytes; the time constant of SERCA-dependent calcium decline when NCX is blocked is about 50% slower in humans (~600 ms) than rabbits (~400 ms).

    “The time constant of SERCA dependent calcium decline alone (when NCX activity is blocked) is about 50 percent slower in humans than rabbits (approximately 600 ms in humans vs. 400 ms in rabbits) (Z. Su, et al., 2003).”
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    • cites Z. Su, et al., 2003

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    Premisecitation

    In rabbit ventricles, SERCA and NCX remove 70-74% and 23-28% of calcium, respectively, similar to human ventricles where SERCA removes 76% and NCX 24%.

    “Rabbit ventricular SERCA and NCX systems are responsible for removing 70–74% and 23–28% of calcium, respectively (Bassani, et al., 1994; Puglisi, Bassani, Bassani, Amin, & Bers, 1996). These values are again similar to the relative activities of SERCA (76%) and NCX (24%) in human ventricles (Piacentino, et al., 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bassani, et al., 1994 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Stimulation frequency affects contractile and relaxation kinetics to some degree.

    “Note that stimulation frequency affects contractile and relaxation kinetics to some degree”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    Humans can raise cardiac output during exercise through both heart rate and stroke volume to a much greater extent than rodents, so human cardiac reserve is much greater than rodent cardiac reserve.

    “humans have a much greater ability than rodents to increase their cardiac output during exercise by both heart rate and stroke volume mediated mechanisms.”
    • Also stated in: § Disadvantages · plain
      “In other words, the cardiac reserve of humans is much greater than rodents.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A mouse typically can increase cardiac output by no more than one-third, while highly trained humans can increase it up to 10-fold.

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    Premisecitation

    There is a high degree of resemblance between human and canine sino-atrial node activity and structure, purkinje fiber distribution, and activation sequence.

    “there is a high degree of resemblance between human and canine sino-atrial (SA) node activity and structure (Review: (Fedorov, Glukhov, & Chang, 2012)), purkinje fiber distribution, and activation sequence (Allison, et al., 2007; Hamlin, 2007).”
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    Premisecitation

    Rabbit heart rate reserve, and consequently cardiac output reserve, is greater than that of mice (~30-40%) and rats (~40-50%) but less than that of humans (~140-170%).

    “although this heart rate reserve (and consequently cardiac output reserve) is more than reserves of mice (~30–40%) and rats (~40–50%), it is still less than the reserve (~140–170%) available in humans (Flamm, et al., 1990; Stratton, et al., 1994).”
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    • cites Flamm, et al., 1990 source

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    • cites Stratton, et al., 1994 source

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    Premisecitation

    This running adaptation was attributed to the running behavior of rabbits in the wild.

    “This observation was attributed to the running behavior of rabbits in the wild (Meng & Pierce, 1990).”
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    • cites Meng & Pierce, 1990

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    Premisecitation

    The Golden Retriever Muscular Dystrophy line develops cardiomyopathy closely resembling affected humans and is considered to better represent cardiac involvement in human DMD than mouse mdx counterparts.

    “One of these lines is the Golden Retriever Muscular Dystrophy (Cooper, et al., 1988) which develops cardiomyopathy with features that closely resemble those of affected humans (Moise, et al., 1991; Valentine, Cooper, de Lahunta, O'Quinn, & Blue, 1988; Valentine, Cummings, & Cooper, 1989) and is considered to better represent cardiac involvement in human DMD than their mouse mdx counterparts (Nakam”
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    • cites Cooper, et al., 1988 source

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    • cites Moise, et al., 1991 source

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    • cites Nakamura & Takeda, 2010

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    Premisecitation

    Calcium handling mechanisms are similar between canine and human: SERCA and NCX contributions to calcium removal are 73% and 27% in canine and estimated 76% and 24% in human.

    “the relative contributions of SERCA and NCX to calcium removal in canine myocardium are 73% and 27% (Bers, 2001) and in human myocardium are estimated to be 76% and 24% (Piacentino, et al., 2003), respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bers, 2001

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    • cites Piacentino, et al., 2003 source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The rabbit heart shares many similarities with the human heart, although some variations exist.

    “The rabbit heart shares many similarities to that of human although some variations exist.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    It is proposed that the effective size of the heart determines ventricular fibrillation pattern, and based on this analysis rabbits have a closer effective size to humans and hence more similar ventricular fibrillation patterns than canines or pigs.

    “it is proposed that the “effective size” of the heart (third root of heart weight divided by spiral wave rotation period) determines ventricular fibrillation pattern. Based upon this analysis, it is argued that rabbits have a closer effective size to humans and hence more similar ventricular fibrillation patterns than either canines or pigs (Panfilov, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Panfilov, 2006 source

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  • May combine two claims.

    Interpretationreasoning

    Even though rabbit and human calcium handling are more closely related than rat and human, the post-rest potentiation phenotype in humans more closely resembles rat.

    “Therefore, even though rabbit and human calcium handling mechanisms are more closely related than those of rat, this particular phenomenon in humans phenotypically more closely resembles that of the rat.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Loss of dystrophin gene product has a profound impact on human hearts while mouse myocardium is only minimally affected.

    “The loss of dystrophin gene product has a profound impact on human hearts while mouse myocardium is only minimally affected.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both compliant N2BA and stiff N2B titin isoforms are expressed in canines (N2BA:N2B ratio ~0.6-1) and humans (ratio ~0.4-1.2).

    “Both compliant N2BA and stiff N2B isoforms are expressed in canines (N2BA:N2B ratio of ~ 0.6–1) and humans (N2BA:N2B ratio of ~0.4–1.2) (Bell, et al., 2000; Cazorla, et al., 2000; Jaber, et al., 2008; Makarenko, et al., 2004; Nagueh, et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bell, et al., 2000 source

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    • cites Cazorla, et al., 2000 source

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    • cites Jaber, et al., 2008 source

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    Premisecitation

    Canine action potential duration is only slightly shorter than human action potential duration and is more comparable than previously discussed animal models (canine APD90 ~219 ms vs human ~290 ms in right ventricular papillary muscles at 1000 ms cycle length and 37 degrees C).

    “The action potential duration of canine is only a little bit shorter than that of humans, much more comparable than the animal models discussed previously (canine APD90: ~ 219 ms, human APD90: ~290 ms both measured in right ventricular papillary muscles at cycle length of 1000 ms and 37 °C) (Szel et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Szel et al. 2011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study of canine force-frequency relationship by Taylor et al. was performed at a sub-physiological temperature of 30 degrees C.

    “We must point out that this particular study was performed at sub-physiological temperature of 30 °C.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor, et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This canine heart rate increase is approximately 96-136%, close to but lower than the 140-170% increase in humans.

    “This reflects an increase of approximately 96–136% which is close-lower than the 140–170% increase in heart rate observed in humans (Flamm, et al., 1990; Stratton, et al., 1994).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Flamm, et al., 1990 source

      Not checked in the free run.

    • cites Stratton, et al., 1994 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Rabbit resting heart rate is considerably higher than human resting heart rate and is near the upper limit of human heart rate even during exercise.

    “the resting heart rate of a rabbit is considerably higher than humans; rabbit resting heart rate is near the upper limit of human heart rate even during exercise conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The same report showed that canine SERCA activity is most comparable to humans, followed by rabbits and then mice.

    “The same report also showed that the canine SERCA activity is most comparable to humans, followed by rabbits and then mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Z. Su, et al., 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The post-rest behavior differences are largely attributed to changes in sarcoplasmic reticulum calcium content during rest, which decreases in rabbits and increases in humans.

    “This has largely been attributed to changes in sarcoplasmic reticulum calcium content during rest periods where rabbits’ and humans’ are decreased and increased, respectively (Maier, Bers, et al., 2000; Pieske, et al., 1999).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Maier, Bers, et al., 2000

      Not checked in the free run.

    • cites Pieske, et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, rabbits are an attractive cardiac research model, balancing higher cost than mice and rats with generally closer biological resemblance to humans.

    “Overall, rabbits are an attractive model in cardiac research, balancing the increased cost when compared to mice and rats with a generally closer biological resemblance to human.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Rabbits cost less to acquire and house than larger animal models such as canine and sheep.
    • Rests on an assumption: Rabbits cost more to acquire and house than mice and rats.

  • May combine two claims.

    Interpretationreasoning

    Canine heart rate is faster than human heart rate during both rest and exercise but closer than previous species discussed.

    “Note that canine’s heart rate is faster than human’s during both rest and exercise conditions but closer than the previous species discussed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Spontaneous mutations in various canines resulting in lack of dystrophin have been identified and canine muscular dystrophy lines are established.

    “Spontaneous occurring mutations in various canines resulting in lack of dystrophin have been identified and canine muscular dystrophy lines are established.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cooper, et al., 1988 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These techniques are not as simple as intraperitoneal and intravenous techniques available in small rodents.

    “As discussed for other large animal models, these techniques are not as simple as the intraperitoneal and intravenous techniques available in small rodents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Swine hearts have in vivo contractile and relaxation kinetics slightly faster than humans but much more similar than small rodents or rabbits.

    “Swine hearts have in vivo contractile and relaxation kinetics that are slightly faster than humans but much more similar than either small rodents or rabbits (Table 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In one study by Yue et al., jugular vein injection of AAV-9 in neonatal dogs successfully transduced skeletal tissue but failed to transduce cardiac muscle.

    “In one study by Yue et al. jugular vein injected AAV-9 in neonatal dogs while successfully transduced skeletal tissue, it failed to do so with cardiac muscle (Yue, et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yue, et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Canine hearts are typically transduced via methods that specifically target the myocardium such as direct intramyocardial and percutaneous transendocardial injections, which are technically more challenging than simple IP and IV methods.

    “Canine hearts are typically transduced via methods that specifically target the myocardium such as direct intramyocardial (Pepe, et al., 2010) and percutaneous transendocardial injections (Bish, Sleeper, et al., 2008) which are technically more challenging than simple IP and IV methods.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pepe, et al., 2010 source

      Not checked in the free run.

    • cites Bish, Sleeper, et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Swine resting heart rates are just slightly higher than humans, while exercise heart rates are moderately higher than achievable in humans.

    “while the resting heart rates are just slightly higher than humans; the exercise heart rates are moderately higher than achievable in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These characteristics make canine and human myocardium behave similarly in response to exercise, making the canine generally a good model for exercise studies in cardiovascular research.

    “These characteristics make canine and human myocardium behave similarly in response to exercise, making the canine generally a good model for exercise studies in cardiovascular research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Other differences between swine and human include small or lack of transient outward current (Ito) in swine and purkinje fiber distribution.

    “Other differences include small or lack of transient outward current (Ito) in swine (Lacroix, et al., 2002; G. R. Li, et al., 2003; Schultz, et al., 2007) and purkinje fiber distribution (Hamlin, 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lacroix, et al., 2002 source

      Not checked in the free run.

    • cites G. R. Li, et al., 2003

      Not checked in the free run.

    • cites Schultz, et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Genetic canine models have a valid role in cardiovascular research and can in most cases significantly better resemble human disease than small rodents.

    “these genetic models have a valid role in cardiovascular research and can in most cases significantly better resemble human disease than small rodents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Heart failure can be induced in swine by rapid pacing and myocardial infarction.

    “Heart failure can be induced in swine by a variety of methods such as rapid pacing (Lacroix, et al., 2002) and myocardial infarction (Pleger, et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lacroix, et al., 2002 source

      Not checked in the free run.

    • cites Pleger, et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One report concluded that swine not only expressed more N2BA than humans, but the N2BA:N2B ratio was more similar to dilated human cardiomyopathy, a condition where N2BA expression is upregulated.

    “one of these reports (Chung, et al., 2011) concluded that not only swine expressed more N2BA than humans, but additionally the N2BA:N2B ratio of this animal model was more similar to dilated human cardiomyopathy, a condition were N2BA expression is upregulated (Makarenko, et al., 2004; Nagueh, et al., 2004).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chung, et al., 2011 source

      Not checked in the free run.

    • cites Makarenko, et al., 2004 source

      Not checked in the free run.

    • cites Nagueh, et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The rationale for pursuing canine studies becomes more convincing if prior studies in small rodents have already established the role of a particular gene, process, or phenomenon in cardiovascular health and disease.

    “The rationale for pursuing these studies in canine becomes more convincing if prior studies in small rodents have already established the role of a particular gene, process, or phenomenon in cardiovascular health and disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite high similarity between human and canine myocardium, some differences have been reported, including resting and exercise heart rates, kinetics of Ito current inactivation, its recovery, molecular size of corresponding ion channels, sensitivity to flecanide, and transmural epicardial:endocardial expression levels of HERG ion channel.

    “Such differences include resting and exercise heart rates (see above), kinetics of Ito current inactivation, its recovery, and molecular size of its corresponding ion channels, sensitivity to flecanide (Akar, et al., 2004), and transmural epicardial:endocardial expression levels of HERG ion channel (Szabo, et al., 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Akar, et al., 2004 source

      Not checked in the free run.

    • cites Szabo, et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some canine heart disease models include sudden cardiac death, rapid pacing induced heart failure, repeated microembolization induced chronic heart failure, and gradual aortic constriction induced left-ventricular pressure-overload.

    “Some of these models include sudden cardiac death (review: (Billman, 2006)), rapid pacing induced heart failure (Recchia, et al., 1998; Sabbah, et al., 1991), repeated microembolization induced chronic heart failure (Sabbah, et al., 1991), gradual aortic constriction induced left-ventricular pressure-overload (Koide, et al., 1997).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Billman, 2006 source

      Not checked in the free run.

    • cites Recchia, et al., 1998 source

      Not checked in the free run.

    • cites Sabbah, et al., 1991

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Collaboration among multiple laboratories can address the limited availability of human samples by using them efficiently.

    “This issue can be addressed by collaboration between multiple laboratories in order to use these samples efficiently.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Human samples are available only in limited quantities.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Sheep have a resting heart rate slightly higher than humans.

    “Sheep have a resting heart rate which is slightly higher than humans (See Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Sheep and other large animals require AAV vector transduction techniques for myocardial tissue, whereas small rodents can receive intraperitoneal and intravenous injections.

    “Another limitation is the need for techniques for transduction of myocardial tissue with AAV vectors (see above) as compared to intraperitoneal and intravenous injections which are feasible in small rodents.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Small rodents allow rapid and inexpensive proof-of-principle experiments.

    “Small rodents can be used to perform proof-of-principle experiments rapidly and cost-efficiently.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Despite evolutionary conservation of many cardiovascular features, differences remain between humans and common laboratory animal models.

    “Despite the preservation and conservation of many aspect of the cardiovascular system during evolution of humans and commonly used laboratory animal models, various differences exist that must be considered.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    An approach combining multiple animal models with verification in human myocardium is essential for advancing cardiovascular research.

    “We believe that an approach that uses multiple animal models with verification using human myocardium is essential in advancing research in the cardiovascular field.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Small and large animal models each have strengths and weaknesses, and all discussed models play an important role in cardiovascular research.

    “Both small and large animal models have specific strengths and weaknesses, and all of the animal models discussed in this manuscript have an important role in cardiovascular research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The most common cause of non-congenital aortic constriction is aortic valve calcification, a gradual process leading to progressive hypertrophy and heart failure.

    “The most common cause of non-congenital aortic constriction is calcification of aortic valve which is a gradual progressive and not sudden process resulting in progressive cardiac hypertrophy and heart failure (Dweck, Boon, & Newby, 2012; Nishimura, 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dweck, Boon, & Newby, 2012 source

      Not checked in the free run.

    • cites Nishimura, 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Human tissues, when available, can further illuminate translational applications for patients.

    “Furthermore, the use of human tissues, if available, can shed further light onto translational applications for human patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    For studying contractile and relaxation kinetics in heart failure, any large animal model is suitable, and economic or logistical factors may guide the choice.

    “On the other hand, if the objective of the study is to understand alterations in contractile and relaxation kinetics in heart failure, any of the large animal models will be appropriate, and the choice may be more dependent on economic or logistical factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both sheep and human hearts have a positive force-frequency relationship.

    “both sheep and human hearts have a positive force-frequency relationship.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LVADs can cause changes and reverse remodeling in myocardium, complicating analysis of failing human samples.

    “These devices can induce some changes and reverse-remodeling in the myocardium (Ambardekar & Buttrick, 2011) which can further complicate analysis of results obtained from failing human samples.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ambardekar & Buttrick, 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Verifying treatments or pharmacological compounds in human tissue would help advance them to clinical trials with minimal patient risk.

    “Since the ultimate goal of biomedical research is to address human health and disease, experimental verification of potential treatment strategies or quantitative verification of novel pharmacological compounds in actual human tissue would further aid in moving treatments to clinical trials with minimal risk to the patient.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sheep and human left ventricles express both major titin isoforms in considerable amounts with N2BA:N2B ratios of ~0.35-0.43 and ~0.4-1.2, respectively.

    “Sheep and human left ventricles express both major titin isoforms in considerable amounts with N2BA:N2B ratios of ~0.35–0.43 and ~0.4–1.2, respectively (Cazorla, et al., 2000; Kruger & Linke, 2006; Makarenko, et al., 2004; Nagueh, et al., 2004; Neagoe, et al., 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cazorla, et al., 2000 source

      Not checked in the free run.

    • cites Kruger & Linke, 2006

      Not checked in the free run.

    • cites Makarenko, et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Cardiovascular studies should not depend on a single animal model to answer all questions.

    “Therefore, studies in cardiovascular system should not rely on a single animal model to address all questions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Whether donor samples can serve as controls depends on the study's objective.

    “Whether these donor samples can be used as control is dependent on the objective of the study.”
    Quote in the paperNot a substantial claim
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?

  • Rodent models are widely used in cardiovascular research due to easy handling and housing, short gestation time, low maintenance costs, and ability for genetic manipulation.

    “Rodent models are widely used in cardiovascular research due to their easy handling and housing, short gestation time, low maintenance costs, and more importantly ability for genetic manipulation.”

    From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [84]

  • The main disadvantage of small animal models (mice, rats, rabbits, and cats) is the relevance of obtained results to humans due to distinct physiological differences.

    “However, the main disadvantage of these small animal models (i.e. mice, rats, rabbits, and cats) is the relevance of the obtained results to humans due to the distinct physiological differences between these species and humans [84–86].”

    From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [84]

  • Infarct size in porcine models can be precisely predicted.

    “infarct size in porcine models can be precisely predicted [84]”

    From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [84]

  • Current animal models, including genetically modified CVD models, cannot fully recapitulate human physiology and pathophysiology and therefore imprecisely predict the biology and mechanisms of human cardiac dysfunction.

    “Current animal models, including genetically modified ones for CVDs, are incapable of fully recapitulating human physiology and pathophysiology, and thus imprecisely predict the biology and mechanisms involved in human cardiac dysfunctions [84].”

    From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [84]

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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