© 1998 American Heart Association, Inc.
Editorial |
Murine Cardiac Function
A Cautionary Tail
Correspondence to David A. Kass, MD, Cardiology Division, The Johns Hopkins Hospital, Halsted 500, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}eureka.wbme.jhu.edu
Key Words: cardiac function • mouse • methodology • physiology
The capacity to selectively mutate genes or create excessive or deleted gene expression in mice has yielded a powerful new approach to structure-function studies of cardiac proteins and their role in heart disease.1 As it happened, the molecular techniques required to generate such animals developed more rapidly than did the methods for studying the chamber physiological phenotype. Mainly because of these methodological limitations, studies to date have often presented hemodynamic data that would fail the standards usually applied in larger species. In particular, heart rates (HRs) and basal levels of systolic contraction are frequently depressed to a substantial degree. It has required a major leap of faith to assume that the physiological differences measured between genetically modified and wild-type animals under such conditions translate to the healthy heart or intact animal. Furthermore, in the understandable rush to assess the impact of molecular manipulations, the careful assessment of normal murine cardiac physiology has been left shortchanged. Only now are we beginning to see the results of such analysis, with evidence growing to support potentially important differences between mice and other mammalian species.2 Such data may be very important for properly interpreting the physiological consequences of targeted genetic manipulations, as reviewed by James et al3 in this issue of Circulation Research.
As with larger animals, compromises can and often must be made to balance the need for adequate control to precisely assess cardiac mechanics and physiological intactness to maintain near-normal physiology. Although conscious animal data are often considered the gold standard in larger species, they are not necessarily required to provide relevant or valuable hemodynamic insights. However, awareness of more intact normal physiology has always been critical to properly interpret data obtained in more invasive or isolated heart studies. Rarely has the discrepancy between conscious animal and anesthetized or isolated heart data been as extreme as it appears to be in the mouse. By highlighting these disparities and their potential causes, we hope to bring the target range for normal murine cardiac function into better focus and stimulate efforts to define basal states in various strains in greater detail.
What Is Normal for the Resting Mouse Heart?
The most direct sign of abnormal chamber function in murine cardiac function assessments has been profound basal bradycardia. Many studies in closed- and open-chest preparations or isolated ventricles have presented data with basal HRs near 300 bpm.4 5 6 7 8 9 Such rates are well below the physiological range for the mouse. Basal HRs in conscious mice are within the range of 550 to 620 bpm.10 11 12 13 14 Thus, most murine studies are reporting cardiac mechanics at resting rates that would correspond to 20 to 40 bpm in a human, and features of cardiac physiology are greatly modified at such slow rates.
Equally important is corresponding evidence of baseline cardiac
depression. The three most commonly reported systolic
parameters are mean arterial pressure, left
ventricular systolic pressure, and the first
derivative of left ventricular pressure
(dP/dtmax). Mean pressure is reported at 100 to
115 mm Hg in conscious mice,11 12 14 15 16 17
with peak systolic pressures near 120 mm Hg. Yet the
majority of murine studies in anesthetized animals report mean
pressures of 
80 mm Hg, with peak systolic pressures in
the same range. Values for baseline dP/dtmax are
typically near 4000 mm Hg/s, with only a few studies reporting
values as high as 9000 mm Hg/s.
The Table
summarizes published data for HR and
dP/dtmax in normal hearts from several mammalian
species in the conscious state. The ratio of
dP/dtmax to HR is seen to be well conserved
between 25 and 30. Thus, mice with resting rates of 550 bpm would be
expected to have a value of dP/dtmax nearer
16 000 mm Hg/s. Although these data have yet to be reported in
fully conscious animals, studies have found such values in mice
awakening from anesthesia,18 and our
laboratory has similarly obtained values near 17 000 mm Hg/s
under such conditions. Importantly, the often reported depressed
dP/dtmax values are not just a reflection of
bradycardia, since pacing such hearts even to
subphysiological rates leads to further
cardiodepression.8 18
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To date, very few alternative systolic function
parameters to dP/dtmax have been
reported for mice. We recently reported several such
parameters derived from pressure-volume relation
analysis, including the end-systolic elastance and
preload-recruitable stroke work.23 24 The latter
parameter (slope of relations between cardiac stroke work
[ie, pressure · volume] and end-diastolic volume) is
particularly useful since it has force (pressure) units and is chamber
scaling-size independent. This parameter was measured in
C3H/HeJ control mice under 
-chloralose/urethane
anesthesia and yielded values in the range of 80 to
100 mm Hg, very similar to values reported in conscious
humans19 and dogs.25
dP/dtmax was 
12 000 mm Hg/s and HRs
were 600 bpm in these same ventricles. These values are likely
closer to those in the conscious state.
Cardiac Reserve Function
There are three principal mechanisms by which cardiac systolic function is enhanced: the force-frequency relation, adrenergic stimulation, and the force-length or Frank-Starling mechanism. Each are typically invoked in humans and larger animal species when increased cardiac performance is needed. To date, studies have not defined the relative role of each mechanism in mice under normal conditions, and existing data suggest that the first two mechanisms may in fact play only a minor role.
Maximal HR reserve as a percentage of baseline HR is known to differ among species. In 1992, Vornanen10 reported that maximal HR induced by exercise was very similar to that observed with maximal isoproterenol stimulation. This was well defined by an allometric equation: HRmax=450 · Mb-0.15, with Mb being body mass in kilograms. Prior studies26 had reported that resting HR was similarly related to body mass by the corresponding equation: HRrest=241 · Mb-0.25. Thus, the ratio of maximal to resting HR is as follows: HRmax/HRrest=1.87 · Mb-0.1.
Fig 1 displays this last relation. For
species at body masses of >1 kg, maximal HR is 2- to 3-fold above
baseline. However, in substantially smaller animals, such as the
mouse,10 maximal HR is 30% above resting
rates. This is consistent with upper rate limits of
actin-myosin crossbridge kinetics that predict maximal rates of 1000
bpm and with experimental data reporting maximal HRs of 720 to 800 bpm
in mice during exercise or with maximal-dose
isoproterenol.10 13 Continuous telemetric
monitoring in conscious mice has yielded HRs of 550 to 600 bpm, with
peak rates observed at night consistent with nocturnal
behavior.11 These results raise doubts about the
role of the force-frequency reserve mechanism in the intact mouse. On
the other hand, the influence of HR on cardiac function is considerable
if one starts at greatly reduced rates, such as those lowered by
anesthesia or by direct pharmacological sinus node
inhibition.18
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A similar word of caution is appropriate when evaluating the role of adrenergic reserve. In hearts with acutely reduced basal HRs and contractility, adrenergic reserve often appears enhanced. Resting vagal tone appears to play a minimal role in modulating HR in mice,16 but sympathetic withdrawal with heart isolation or anesthesia could greatly contribute to resting cardiodepression and bradycardia. The resultant adrenergic reserve would likely be very different if compared in animals with normal basal dP/dtmax nearer 17 000 mm Hg/s. Cardiac effects from molecular manipulations of adrenergic signaling or excitation-contraction coupling proteins could also be amplified in preparations with reduced sympathetic stimulation. This may underlie discrepancies between the lack of long-term morbidity or mortality found in a number of genetically engineered models influencing excitation-contraction coupling and adrenergic signaling and more pronounced physiological differences in the isolated and anesthetized hearts from these same animals.
Chamber Loading
Although dP/dtmax is the most widely used measure of murine cardiac systolic function, this parameter has well-recognized loading sensitivities, primarily from preload change.27 28 At low levels of mean arterial pressure, dP/dtmax also has afterload dependence.27 Interventions that alter cardiac chamber filling volumes (such as vasodilators and HR changes) may thereby alter dP/dtmax. This has been well characterized in the canine heart, but there has been, as yet, little study of dP/dtmax load dependence in the murine heart.
Recent data suggest that such dependence is considerable.23 24 For example, in C3H/He and C57BL6 strains, reducing end-diastolic pressure (EDP) by only 1 mm Hg from resting baseline is sufficient to lower dP/dtmax by 18±5.2%. Thus, unless EDP can be accurately and reliably measured to a precision of <1 mm Hg, it may be difficult to ensure that dP/dtmax changes were not influenced by preload on the basis of the EDP.
Fig 2 displays an example of the load
sensitivity of dP/dtmax in a mouse under control
conditions and during intravenous infusion of
propranolol. There is substantial
dP/dtmax load sensitivity, with a 23% decline
(-3300 mm Hg/s, dotted line) corresponding to a <1 mm Hg
EDP change in the control condition. Furthermore, as shown by the
change in the relation slope with propranolol, this load
sensitivity varies with inotropic state. Thus, an intervention that
enhances contractility also increases the preload
sensitivity of dP/dtmax. If this intervention
also leads to a decline in EDP of only 1.5 mm Hg (close to the
noise level), this contractile change could be greatly underestimated
(arrow). Alternatives, such as the slope of the
dP/dtmax-EDP relation as shown in Fig 2, may be
valuable in this regard.
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Anesthesia and Ventilation
Undoubtedly, major contributors to basal cardiac depression in the in vivo murine ventricle are both the type of anesthesia and mode of ventilation. The anesthesia used in a majority of studies has either been a combination of xylazine with ketamine or 2,2,2-tribromo-ethanol (avertin). Many studies using the former have yielded data with low systolic pressures and bradycardia, so it appears not recommendable for mice. 2,2,2-tribromo-ethanol has been reported to raise postanesthesia mortality to 35% within 3 months29 and is also a cardiodepressant. There is also considerable interstrain differences in anesthesia sensitivity, and careful adjustments are required for each strain. This can complicate studies in which strains have been combined to a varying and often unknown extent, such as the very commonly used C57BL/6xSV129 strain.
Several forms of anesthesia appear to be better tolerated
and yet are infrequently used. One is -chloralose/urethane, which
has minimal effects on cardiovascular reflexes and
appears to be well tolerated in mice.30 Our
experience with this agent supports its use even in open-chest
preparations, yielding physiological HRs of 550 to
600 bpm, systolic pressures at or above 100 mm Hg, and
dP/dtmax values of 12 000 mm Hg/s or
more.23 24 One disadvantage is that this agent is
not generally used for survival procedures. Alternatives such as
inhaled methoxyflurane29 or etomidate given at a
dose of 20 to 30 mg/kg IP are both well tolerated, yield
physiological HRs and blood pressures, and are
fully compatible with recovery. More attention to optimizing the use of
anesthetics in murine studies is clearly needed.
Close attention also needs to be paid to methods and patterns of
artificial ventilation. Ventilation is not provided at all in some
studies but is administered by a volume respirator in others, and there
is remarkable variability with respect to the ventilation rate and
tidal volumes used, with little to no assessment of its adequacy. Mice
spontaneously breath at rates between 160 and 280 bpm, with tidal
volumes of 160 µL, yielding a minute ventilation of 1.2 mL
· min-1 ·
g-1.11 31 These values
also vary between strains. Conscious murine ventilation occurs with an
elevated functional residual capacity (FRC) that is due to expiratory
braking from persistent inspiratory muscle activity and/or increased
glottal resistance.32 In anesthetized
animals, loss of this braking mechanism along with reduced tidal volume
and frequency can lower the FRC to near relaxation volumes, with a
resultant risk of atelectasis. The latter is further assisted by very
high chest wall compliance,33 which, although
useful for enabling the animals to squeeze under doorways, likely
contributes to airway collapse under anesthesia.
Furthermore, the hemoglobin-oxygen dissociation curve in mice is
shifted substantially rightward (the partial pressure at 50%
hemoglobin saturation [P50] is 27 mm Hg for humans
versus 65 mm Hg for mice) compared with other mammalian
species.34 Thus, room air ventilation may not be
ideal and could contribute to cardiovascular
depression. More attention should be paid to inflation pressures,
making sure that overinflation and underinflation are not occurring.
Normal airway flow pressures should be between 5 and 10
cm/H2O. One should carefully assess
pulmonary ventilatory mechanics in each preparation and take
efforts to optimize ventilation.
The Challenge
Only a decade ago, few if any investigators could have imagined the intense interest that would develop around assessing cardiovascular function of mice. New techniques are evolving, and better methods will undoubtedly appear in the near future. At present, however, one too often comes across hemodynamic data far removed from physiological operating ranges, with control data falling short of this claim. The concern is that such abnormal baselines bias assessments of genetic manipulations to overestimate or underestimate their real influence. It is certainly possible that studying murine hearts under these conditions indeed yields data relevant to intact larger mammalian physiology and pathophysiology, but this remains an assumption that needs testing. It is hoped that greater attention to these issues and to characterizing truly normal murine cardiac function, potentially in intact unanesthetized mice, will clarify these assumptions.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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M. Reyes, G. L. Freeman, D. Escobedo, S. Lee, M. E. Steinhelper, and M. D. Feldman Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart: Blunting of Length-Dependent Activation Circulation, June 17, 2003; 107(23): 2962 - 2968. [Abstract] [Full Text] [PDF]
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 E. Aasum, A. D. Hafstad, D. L. Severson, and T. S. Larsen Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From db/db Mice Diabetes, February 1, 2003; 52(2): 434 - 441. [Abstract] [Full Text] [PDF]
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T. Shiomi, H. Tsutsui, S. Hayashidani, N. Suematsu, M. Ikeuchi, J. Wen, M. Ishibashi, T. Kubota, K. Egashira, and A. Takeshita Pioglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction Circulation, December 10, 2002; 106(24): 3126 - 3132. [Abstract] [Full Text] [PDF]
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C. J. Zuurbier, V. M. Emons, and C. Ince Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics, fluid support, and strain Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2099 - H2105. [Abstract] [Full Text] [PDF]
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J. E. Olgin and S. Verheule Transgenic and knockout mouse models of atrial arrhythmias Cardiovasc Res, May 1, 2002; 54(2): 280 - 286. [Abstract] [Full Text] [PDF]
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 G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al. From the Cover: Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a PNAS, April 30, 2002; 99(9): 6210 - 6215. [Abstract] [Full Text] [PDF]
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Q. Liang, E. C. Carlson, R. V. Donthi, P. M. Kralik, X. Shen, and P. N. Epstein Overexpression of Metallothionein Reduces Diabetic Cardiomyopathy Diabetes, January 1, 2002; 51(1): 174 - 181. [Abstract] [Full Text] [PDF]
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C. Y. T. Hart, J. C. Burnett Jr., and M. M. Redfield Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1938 - H1945. [Abstract] [Full Text] [PDF]
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T. Opthof Function and structure of the mouse sinus node: nothing you can see that isn't shown Cardiovasc Res, October 1, 2001; 52(1): 1 - 4. [Full Text] [PDF]
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D. Georgakopoulos and D. A Kass Minimal force-frequency modulation of inotropy and relaxation of in situ murine heart J. Physiol., July 15, 2001; 534(2): 535 - 545. [Abstract] [Full Text] [PDF]
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S. Takuma, K. Suehiro, C. Cardinale, T. Hozumi, H. Yano, J. Shimizu, S. Mullis-Jansson, R. Sciacca, J. Wang, D. Burkhoff, et al. Anesthetic inhibition in ischemic and nonischemic murine heart: comparison with conscious echocardiographic approach Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2364 - H2370. [Abstract] [Full Text] [PDF]
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D. L Lerner, M. A Beardslee, and J. E Saffitz The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia Cardiovasc Res, May 1, 2001; 50(2): 263 - 269. [Full Text] [PDF]
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K. Suehiro, S. Takuma, C. Cardinale, T. Hozumi, J. Shimizu, H. Yano, M. R. Di Tullio, J. Wang, C. R. Smith, D. Burkhoff, et al. Assessment of segmental wall motion abnormalities using contrast two-dimensional echocardiography in awake mice Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1729 - H1735. [Abstract] [Full Text] [PDF]
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 R. W. Sze and K. E. Yutzey The Molecular Genetic Revolution in Congenital Heart Disease Am. J. Roentgenol., March 1, 2001; 176(3): 575 - 581. [Full Text] [PDF]
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V. P. Chacko, F. Aresta, S. M. Chacko, and R. G. Weiss MRI/MRS assessment of in vivo murine cardiac metabolism, morphology, and function at physiological heart rates Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2218 - H2224. [Abstract] [Full Text] [PDF]
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M. D. Feldman, J. M. Erikson, Y. Mao, C. E. Korcarz, R. M. Lang, and G. L. Freeman Validation of a mouse conductance system to determine LV volume: comparison to echocardiography and crystals Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1698 - H1707. [Abstract] [Full Text] [PDF]
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 S. Rao and A. S. Verkman Analysis of organ physiology in transgenic mice Am J Physiol Cell Physiol, July 1, 2000; 279(1): C1 - C18. [Abstract] [Full Text] [PDF]
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J. James, A. Sanbe, K. Yager, L. Martin, R. Klevitsky, and J. Robbins Genetic Manipulation of the Rabbit Heart via Transgenesis Circulation, April 11, 2000; 101(14): 1715 - 1721. [Abstract] [Full Text] [PDF]
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U. Schmidt, F. del Monte, M. I. Miyamoto, T. Matsui, J. K. Gwathmey, A. Rosenzweig, and R. J. Hajjar Restoration of Diastolic Function in Senescent Rat Hearts Through Adenoviral Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase Circulation, February 22, 2000; 101(7): 790 - 796. [Abstract] [Full Text] [PDF]
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 J. E. HUNGERFORD, W. C. SESSA, and S. S. SEGAL Vasomotor control in arterioles of the mouse cremaster muscle FASEB J, January 1, 2000; 14(1): 197 - 207. [Abstract] [Full Text]
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H. C. Champion, D. J. Villnave, A. Tower, P. J. Kadowitz, and A. L. Hyman A novel right-heart catheterization technique for in vivo measurement of vascular responses in lungs of intact mice Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H8 - H15. [Abstract] [Full Text] [PDF]
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C. C. Lim, R. Liao, N. Varma, and C. S. Apstein Impaired lusitropy-frequency in the aging mouse: role of Ca2+-handling proteins and effects of isoproterenol Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H2083 - H2090. [Abstract] [Full Text] [PDF]
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L. E. Rohde, A. Ducharme, L. H. Arroyo, M. Aikawa, G. H. Sukhova, A. Lopez-Anaya, K. F. McClure, P. G. Mitchell, P. Libby, and R. T. Lee Matrix Metalloproteinase Inhibition Attenuates Early Left Ventricular Enlargement After Experimental Myocardial Infarction in Mice Circulation, June 15, 1999; 99(23): 3063 - 3070. [Abstract] [Full Text] [PDF]
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D. L Miller and D. M Van Winkle Ischemic preconditioning limits infarct size following regional ischemia-reperfusion in in situ mouse hearts Cardiovasc Res, June 1, 1999; 42(3): 680 - 684. [Abstract] [Full Text] [PDF]
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G. A. Papadatos, P. M. R. Wallerstein, C. E. G. Head, R. Ratcliff, P. A. Brady, K. Benndorf, R. C. Saumarez, A. E. O. Trezise, C. L.-H. Huang, J. I. Vandenberg, et al. From the Cover: Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a PNAS, April 30, 2002; 99(9): 6210 - 6215. [Abstract] [Full Text] [PDF]
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C. J. Zuurbier, V. M. Emons, and C. Ince Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics, fluid support, and strain Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2099 - H2105. [Abstract] [Full Text] [PDF]
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