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1 Department of Medicine, Houston Veterans Affairs Medical Center, and 2 Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Measurement of left ventricular (LV)
function is often overlooked in murine studies, which have been used to
analyze the effects of genetic manipulation on cardiac phenotype. The
goal of this study was to address the effects of changes in LV
contractility on indexes of contractility in mice. LV function was
assessed in vivo in closed-chest mice by echocardiography and by LV
catheterization using a conductance pressure-volume (P-V) catheter with
three different interventions that alter contractility by 1)
atrial pacing to increase inotropy by augmentation of the
force-frequency relation (modest increment of inotropy), 2)
dobutamine to maximize inotropy, and 3) esmolol infusion to
decrease contractility. Load-independent parameters derived from P-V
relations, such as slope of end-systolic P-V relations (ESPVR) and
slope of the first maximal pressure derivative over time
(dP/dtmax)-end-diastolic volume relation (dP/dt-EDV), and standard echocardiographic parameters were
measured. The dP/dt-EDV changed the most among parameters
after atrial pacing and dobutamine infusion (percent change, 162.8 ± 95.9% and 271.0 ± 44.0%, respectively). ESPVR was the most
affected by a decrease in LV contractility during esmolol infusion
(percent change, 
49.8 ± 8.3%). However, fractional shortening
failed to detect changes in contractility during atrial pacing and
esmolol infusion and its percent change was <20%. This study
demonstrated that contractile parameters derived from P-V relations
change the most during a change in LV contractility and should
therefore best detect a small change in contractility in mice. Heart
rate has a modest but significant effect on P-V relationship-derived
indexes and must be considered in the evaluation of murine cardiac physiology.
contractile indexes; echocardiography; catheterization; mouse heart
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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GENETICALLY ENGINEERED murine models of heart failure have long been used to analyze the effects of a specific genetic manipulation on cardiac phenotype because they impute a cause-and-effect relationship between the candidate gene and the outcome of its manipulation. In phenotypes producing severe ventricular dysfunction, ejection performance is an adequate description of function, but when less severe contractile abnormalities are produced, more accurate measurements of cardiac performance are required, especially in the detection of early changes in contractility. Many approaches to measuring murine cardiac function have been reported. Echocardiography was established early in the history of transgenic models (19) and it has been a useful and convenient tool in evaluating left ventricular (LV) function (11, 21). Recently, the progress in microsurgery and biomedical engineering enabled measurement of LV pressure-volume (P-V) relations in murine models using a combined pressure and conductance transducers (4, 9). This method allows assessment of LV function more precisely by several load-independent indexes, such as maximum elastance (Emax) and the slope of the end-systolic P-V relation (ESPVR). However, which parameters best represent cardiac performance is not clear, especially in detecting small changes in contractility. Although comparative studies examining the influence of various loading and inotropic conditions on indexes of LV contractility based on PV relationships were performed in dogs (13), there is no such study in a murine model, especially comparing contractility indexes derived from echocardiography to those from PV relationships.
The goal of this study was to address the effects of a
change in contractility on indexes of LV contractility in mice. We assessed the sensitivity of contractile indexes to the following three interventions to alter cardiac contractility: 1)
using an atrial pacing increase in heart rate (HR), which has a modest effect on contractility via the force-frequency relation (FFR) (8, 10, 12, 16); 2) using infusion of an
inotropic agent, dobutamine (
-adrenergic agonist), which maximizes
contractility; and 3) using an esmolol (-adrenergic
antagonist) infusion to decrease contractility.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Thirty-four male C57BL mice (12-24 wk) were used in this study. The experimental protocol was approved by the Animal Subjects Committee of Baylor College of Medicine and Houston Veterans Affairs Medical Center. All the animals in this study received humane care in compliance with the animal use principles of the American Physiological Society and the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the National Institutes of Health's Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985).
Animal Preparation and Procedures
Surgical procedures. Mice were anesthetized with a mixture of ketamine (100 mg/kg ip), xylazine (2.5 mg/kg ip), and heparin (5,000 U/kg ip) and additional smaller doses were given as needed. Animals were placed in supine position on a temperature-controlled surgical table to maintain rectal temperature at 37°C and were allowed to breathe spontaneously with 1 l/min of oxygen via nasal cone. Under a dissecting microscope (model SZ40, Olympus; Tokyo, Japan), the right jugular vein was isolated, and a 1-Fr bipolar pacing catheter (model EP118-2, NuMED; Hopkinton, NY) or a polyethylene-10 tube for dobutamine or esmolol infusion was advanced into the right atrium and secured with 8-0 Prolene (model M8753, Ethicon; Somerville, NJ). Atrial pacing was established using a stimulator (model SD9E, Grass Medical Instruments; Quincy, MA). For LV catheterization, the right carotid artery was dissected and cannulated with a 1.4-Fr micro-tipped combined PV catheter (model SPR-719, Millar Instruments; Houston, TX). The conductance catheter was advanced retrograde into the LV and secured with the 8-0 Prolene. The conductance catheter was positioned in the LV chamber as the proximal electrodes of the catheter were positioned below the aortic valve by monitoring the two-dimensional (2-D) parasternal LV long axis imaged using echocardiography. The conductance signal was acquired online using data-acquisition software (BioBench version 1.0, National Instrument; Austin, TX) and analyzed off-line by analysis software (PVAN, version 2.7, 001-1031, Millar Instruments).
Echocardiography
The mice were placed in a slight left lateral decubitus position, and the transducer was placed on the chest while excessive pressure was carefully avoided. Transthoracic echocardiographic examinations were performed using a cardiac system equipped with a 15-MHz linear transducer (Sequoia C256 and 15L8, Acuson; Mountain View, CA). The 2-D parasternal LV long-axis images were obtained at the plane of the aorta and mitral valve with adequate visualization of the LV apex and the short-axis view was recorded at the level of the papillary muscles. After the short-axis view was ensured, 2-D targeted M-mode tracings were recorded through the anterior and posterior LV walls at a sweep speed of 200 mm/s. Pulsed-wave Doppler signals of LV outflow were obtained from apical four-chamber view and were recorded at a sweep speed of 200 mm/s. All images were digitally acquired and stored for off-line analysis.Protocols
Pacing study. DETERMINATION OF HR AT WHICH LV PRESSURE DERIVATIVE OVER TIME IS MAXIMAL IN FFR.
To achieve a modest increment of inotropy, the hearts were atrial paced to a HR (HRmax) at which the first derivative of LV pressure (LVP) over time (dP/dt) was maximal by augmentation of the FFR. Although it has been reported that myocardial contraction and relaxation were enhanced modestly (13-15%) at HRs of 400-500 beats/min (8), five mice were used to define HRmax in this experimental setting because HRmax may differ significantly between strains of mice and between experimental conditions (11, 12, 16). When hemodynamic stability was ensured after the insertion of pacing and conductance catheters, baseline data were recorded. Atrial pacing was then initiated at just above the sinus rhythm (SR) HR and was increased at 1-Hz increments until maximum dP/dt (dP/dtmax) was visually decreased. The setting of the stimulator was 3 V with 2 m/s pulse-width duration. ECHOCARDIOGRAPHY AT SR AND HRMAX. Six mice were studied. Echocardiography was performed during the intrinsic SR and atrial pacing at HRmax. LV CATHETERIZATION AT SR AND HRMAX. Another five mice were used in this LV catheterization protocol. After surgery and hemodynamic stabilization, baseline measurements were performed at SR. After atrial pacing was established at HRmax and hemodynamic stability was ensured, a second set of measurements were performed. A small transverse abdominal incision was then made on the upper abdominal wall, and P-V relations were measured at HRmax by transient occlusion of the inferior vena cava (IVC) with simple compression with the use of a cotton swab. Another set of P-V relation measurements were repeated at SR after termination of pacing and hemodynamic stabilization.Dobutamine infusion study.
Twelve mice were entered into this protocol. Echocardiography and
catheterization were performed individually in two separate groups (6 mice in each group). After baseline measurements dobutamine was infused
at a rate of 30 ng · g body
wt
1 · min1 through
the right jugular vein. When hemodynamic stability was ensured during
infusion, a second set of measurements were made.
Esmolol infusion study.
Eleven mice (5 for echocardiography and 6 for catheterization
individually) were used in this protocol. After baseline measurements, esmolol (ultrashort acting -adrenergic antagonist) was infused intravenously at a rate of 10 mg · kg body
wt · min1. This dose was defined in
a pilot study using five mice. The criteria were to achieve a 10%
decline in HR, a 30% decline in dP/dt, and reversibility of
the effects after completion of the infusion.
Data Analysis and Contractile Parameters
Echocardiography.
M-mode LV internal chamber dimension and posterior wall thickness were
measured at end diastole (EDD) and end systole (ESD) using the
leading-edge method of three consecutive cardiac cycles (6). End diastole was defined at the peak of the QRS
complex of the electrocardiogram. End systole was defined as the peak of posterior wall thickening. LV fractional shortening (%FS) in the
minor axis was calculated as %FS = (EDD ESD) × 100/EDD. LV volume at end diastole (EDV) and end systole (ESV) were
calculated by the bullet method as EDV = 0.85 × CSA(d) × L(d) and ESV = 0.85 × CSA(s) × L(s), where CSA(d) and CSA(s) are endocardial
cross-sectional areas in end diastole and end systole, respectively,
obtained from short-axis view at the level of the papillary muscles and L(d) and L(s) are the LV length (apex to
midmitral annulus plane) in end diastole and end systole, respectively,
obtained from the parasternal long-axis view. LV ejection fraction
(EF%) was then calculated as EF% = (EDV ESV) × 100/EDV.
Ejection time (EjT) was determined from the actual pulsed-wave Doppler
tracings of LV outflow by measuring the interval from the beginning of
the acceleration to the end of the deceleration. The myocardial
velocity of LV circumferential shortening (Vcf)
was calculated as Vcf = [(EDD ESD)/EDD]/EjT, where Vcf is in circumferences
per second and EjT is in seconds. Mean normalized systolic ejection
rate (MNSER) was calculated as MNSER = [(EDV ESV)/EDV]/EjT, where MNSER is in ejections per second.
Vcf and MNSER were used to assess LV ejection performance.
Catheterization-derived indexes. The 1.4-Fr high-fidelity micromanometer catheter was calibrated with a mercury manometer at the beginning of each experiment. Baseline zero reference was obtained by placing the sensor in normal saline before insertion. LVP, HR, and ±dP/dtmax were determined with analysis software. Although dP/dtmax has been widely used as a cardiac contractile parameter in murine cardiac physiology, it is well recognized that dP/dtmax is load dependent, especially on changes in preload (13, 14). On the other hand, previous studies (13, 14) have demonstrated that the slope of the dP/dtmax-EDV relation (dP/dtmax-EDV) represents a sensitive but less load-dependent parameter of chamber contractility. In previous studies, the slope of this relationship increased and shifted leftward with increased contractility, and it decreased and shifted rightward with depressed contractility. ESPVR and Emax also have been used historically to assess in vivo contractility. Although limited by dependence on cardiac size (if the heart increases in volume, ESPVR will decrease regardless of contractility) (2, 15, 18), ESPVR and Emax are thought to be ideal in acute studies such as this one because the heart size, mass, and volume do not change throughout the study. Therefore, ESPVR, Emax, and dP/dt-EDV were used to evaluate in vivo load independent LV contractile performance.
The relative volume unit (RVU) calibrator (Millar Instruments) was used in this study to convert acquired voltage to resistance or relative volume units. Because resistance is the inverse of conductance, conductance was available. However, we instead chose to leave our acquired signal in resistance units because they approximate the blood volume. Because they do not represent absolute volume (because the myocardial contribution to the voltage signal has been ignored) we have used RVU to label the volume axis. Calibration of the offset has been previously performed by hypertonic saline dilution method to measure parallel conductance volume (Vp) (1, 5) and by matching of stroke volume (SV) to an independent standard (
)
(5). However, in our study, with the use of a closed-chest
model, Vp from surrounding organs, which is the offset term
for calibration, varied widely by the amount and speed of the saline
injection (data were not shown). Whereas the dominant source of
Vp in mice is the LV wall itself and varies little with changes in RV volume (9), Vp at steady-state
condition significantly increased when afterload was increased even in
the same mice (5). Moreover, because saline injection
alters hemodynamics in the mouse, dual- frequency excitation is
recommended to measure more accurate Vp (4)
but is commercially unavailable at this time. The lack of the offset
calibration has the disadvantage of failing to give precise estimation
of volume intercepts of P-V relations but the slope of ESPVR,
Emax, and dP/dt-EDV are independent
of this calibration. For all of these reasons, we did not believe the
Vp calculation would improve the accuracy of our measurements.
A correction for electric field inhomogeneity () is relevant to the
slope of ESPVR and could change under different conditions affecting
our results. was calculated as echocardiography-derived SV/conductance SV in this study. The echocardiography-derived SV was
calculated as aortic VTI × CSA, where VTI is the velocity time
integral by Doppler and CSA of the aortic valve by M-mode echocardiography. before/after pacing and off/on dobutamine was
8.03 ± 0.49/7.97 ± 0.36 [not significant (NS),
P = 0.93] and 7.81 ± 0.30/7.82 ± 0.12 (NS,
P = 0.97), respectively. off/on esmolol was
11.50 ± 0.62/10.56 ± 0.74 (NS, P = 0.37).
Although we used the same design of catheter in the esmolol protocol,
the catheter had a different . Importantly, although varied
between catheters with different serial numbers, it was consistent with and without interventions in each protocol. Therefore, changes in
parameters derived from PV relationships using three interventions were
not affected by an intervention-induced change in in our studies.
To detect sensitivity of parameters to change in contractility, the
percent change was calculated in all derived parameters as {[(value
during the pacing or dobutamine infusion) (baseline value)] × 100}/(baseline value).
Statistics
Data are expressed as means ± SE. Hemodynamic data were compared between baseline and during interventions in each protocol using a paired t-test. One-way analysis of variance (ANOVA) was used to compare the percent change in contractility between parameters. Data were further compared by Student-Newman-Keuls test whether ANOVA was significant. A P < 0.05 was considered statistically significant.| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Determination of HRmax
Incremental atrial pacing resulted in a significant increase and biphasic change in dP/dtmax (Fig. 1). HRmax was 505 ± 14 beats/min. We therefore used 505 beats/min as HRmax for the pacing study protocol.
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Pacing Study
Hemodynamic parameters at both HRs were shown in Table 1. Figure 2 shows the percent change of the indexes in the mice. All parameters except for %FS showed a significant change. The dP/dt-EDV was the most affected (162.8 ± 95.9% increase) by a change in LV contractility, followed by Emax (67.9 ± 12.2% increase). The percent change in the dP/dt-EDV was significantly greatest among the parameters. Echocardiography-derived global systolic parameters, such as %FS and EF%, had very small percent changes (10.2 ± 6.3% and 16.6 ± 5.3%, respectively). The dP/dt at HRmax versus SR (8,549 ± 780 and 6,080 ± 715 mmHg/s, respectively, P < 0.05) also increased significantly. The percent change in ejection performance expressed as Vcf and MNSER (42.2 ± 8.0% and 51.9 ± 5.6%, respectively) significantly increased after the pacing.
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Dobutamine Study
Hemodynamic parameters at baseline and during dobutamine infusion were shown in Table 2. Figure 3 shows the percent change of the indexes. Dobutamine significantly increased contractile parameters with a large percentage of change except for ESPVR and Emax, where changes were inconsistent during dobutamine infusion. Again, dP/dt-EDV was the most affected (271.0 ± 44.0% increase) by changes in LV contractility among the parameters and was followed by Vcf and MNSER (103.5 ± 23.6% and 71.3 ± 4.8%, respectively).
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Figure 4 shows a representative
echocardiogram during dobutamine infusion and IVC occlusion, which
explains the inconsistency in ESPVR. The proximal pair of electrodes
was moved out from the small LV cavity during this maneuver. Figure
5 shows representative P-V loops during
dobutamine infusion and IVC occlusion. All loops have a spike
at the corner of end systole, which indicates interference between
pressure manometer and the LV endocardial surface. The lowest P-V loops
shift to the right of the ESPVR line because the proximal sensing
electrodes were positioned above the aortic valve. These anatomic
findings were observed only during dobutamine infusion, which caused
tachycardia and small ventricular cavity in end systole.
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Esmolol Study
Hemodynamic and LV functional parameters at baseline and during esmolol infusion are shown in Table 3. Figure 6 demonstrates the percent change of the contractile indexes. Although esmolol significantly reduced LV contractility detected by catheterization-derived indexes, %FS and EF% failed to detect the changes in contractility. The percent change in %FS, EF%, Vcf, and MNSER were very small (%change:8.7 ± 3.9, 11.4 ± 4.9, 14.5 ± 3.0, and 14.8 ± 3.9, respectively) and
consistent with those in the pacing protocol. Interestingly, ESPVR was
the most affected among the indexes (%change: 49.8 ± 8.3) but
was not significantly greater than the change in
Emax and dP/dt-EDV (%change:
41.9 ± 10.9 and 40.8 ± 10.7, respectively).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There were four major findings of this study. First, load-independent parameters derived from P-V relationships were the most affected by a change in LV contractility. Second, %FS failed to detect the changes in contractility produced by pacing and esmolol infusion. Third, HR has a modest but significant effect on murine LV contractility measured by P-V relation-derived parameters at relatively lower HR in this study. Fourth, the catheter used in this study caused artifactual malpositioning of the electrodes outside the small LV cavity caused by dobutamine infusion.
Echocardiographic Indexes
FS has been used in many murine studies because it is convenient and easy to understand. %FS is most useful in studies of transgenes, which have caused dramatic changes in cardiac phenotype. In our study, dobutamine, a strong inotrope, caused a significant change in %FS. However, %FS could not detect the difference in contractility increased by pacing at HRmax or decreased during esmolol infusion. These results suggest that %FS would be ineffective in detecting small changes in contractility in murine models. In contrast, both mean Vcf and MNSER consistently showed a significant change in all three settings of this study. However, because both indexes are also afterload sensitive (10, 21), the relation with end-systolic stress needs to be assessed when a significant difference in the wall stress among groups is expected, such as in severe hypertrophy and hypertension.Catheterization Indexes
Pacing at HRmax or dobutamine significantly increased dP/dtmax compared with baseline in this study. On the other hand, dP/dtmax was significantly decreased during esmolol infusion. However, caution must be used in assessing LV contractility using dP/dtmax because of substantial load dependence (9). Georgakopoulus et al. (7-9) showed that reducing EDP by only 1 mmHg from resting baseline was sufficient to lower dP/dtmax by 18 ± 5.2%. Thus parameters of LV contractile performance independent from or corrected for preload, such as ESPVR and Emax (18) and dP/dtmax-EDV (14) established in larger animals, are also needed in making murine measurements of contractility. Whereas these parameters can be defined only by simultaneous measurement of pressure and volume, technical advances of microtipped combined PV catheters in the mouse have made it possible to obtain these parameters in vivo. These parameters increased significantly at HRmax and decreased significantly during esmolol infusion. The slope of dP/dtmax-EDV changed the most among the parameters we studied in the pacing and the dobutamine studies. This finding was supported by a previous report using an isolated canine heart model with carefully controlled alterations in preload and afterload. The dP/dt-EDV appeared an excellent choice to address contractility because of its marked sensitivity to inotropic change, its lack of preload dependence, and its minimal afterload dependence in the physiological range (13). On the other hand, in the current study, dP/dt-EDV changed similarly to ESPVR and Emax during esmolol infusion. The possible explanation in the differential response of dP/dt-EDV between positive and negative inotropy remains unclear.In the dobutamine infusion protocol, the end-systolic parameter Emax failed to show significant increase and consistent percent change. As seen in Fig. 4, the small LV cavity caused malpositioning of the catheter electrodes outside the LV cavity, which led to an artifact on the volume signal (Fig. 5). Therefore, caution must be used in assessing ESPVR parameters in small LV cavities using the P-V catheter that we used in this study. In future catheter redesign, spacing electrodes for small LV size will obviate this problem.
In this study, the lack of the offset calibration had the disadvantage of failing to give a precise estimation of volume intercepts (Vo) of PV relations. Because Vo varies under different loading conditions (e.g., afterload shifts Vo to the left, whereas preload shifts it to the right), it is valuable to determine Vo in the P-V plane analysis. Therefore, the results of P-V relation-derived parameters in this study will need to be verified when dual frequency conductance system is available.
Effects of HR on Cardiac Performance in Mice
In the present study, HR was used to assess the effect of a modest inotropic stimulus on performance based on the known effects on force of increasing frequency. Georgakopoulos and Kass (8) reported that contraction (dP/dtmax) and relaxation (time constant of isovolumic relaxation,
) were enhanced
modestly (13-15%) at HRs of between 400 and 500 beats/min and
ESPVR rose 35% at HRs from 400 to 600 beats/min. We noted similar
changes in FFR and ESPVR. Georgakopoulos and Kass (8)
noted that within the broad physiological HR (500-850 beats/min),
by normalizing dP/dtmax by instantaneous
developed pressure to diminish preload dependence, the biphasic
HR-dP/dt relationship, especially the descending limb of the
regular FFR, become flat. Accordingly, there was very little change in
ESPVR at HRs >500 beats/min (8). They concluded that the
normal mouse has a very limited force-frequency reserve at
physiological HRs unlike larger mammals. Interestingly, however, although we did not test the effects of a wide range of physiological HRs on contractile function, the HR at which the normalized FFR plateaued (~500 beats/min) in the previous study (8) was
similar to HRmax in this study.
The positive inotropic response in the upslope of FFR is possibly explained by an increase in Ca2+ availability to the contractile filaments as a result of increased Ca2+ storage in the sarcoplasmic reticulum (SR) with augmentation of subsequent Ca2+ transients (20). Interestingly, it is demonstrated that the recirculation fraction of Ca2+ was 93 ± 1% in intact mice (much higher than the 50% in larger animals), which implies a more dominant role of SR buffering compared with other source of Ca2+ (8). It is also widely known that depressed FFR with abnormal Ca2+ handling by the sarcoplasmic reticulum and the Na+/Ca2+ exchanger pump play a major role in human (17) and experimental heart failure (22). Therefore, it is not surprising that FFR and HRmax can vary in different settings of heart failure and in various transgenic mice in which gene modification affects intracellular Ca2+ homeostasis and SR function.
In conclusion, contractile parameters derived from P-V relations are most sensitive to change in LV contractility and should be used especially to detect a small change in contractility. This study also identified limitations of echocardiographically derived %FS in the response to a modest change in contractility. However, caution must be exercised for assessment of ESPVR and Emax in small LV cavities because of possible malpositioning of catheter electrodes above the aortic valve. Moreover, HR has a substantial effect on murine LV performance at subphysiological HRs and HRmax must be used in the evaluation of cardiac function.
Limitations
All measurements in this study are performed during acute changes in contractility. Whereas it is well known that end-systolic indexes derived from P-V relations are changed by chronic changes in volume and mass regardless of contractility in larger animals (15, 18), how this concept applies to genetically altered mice with chronic cardiovascular changes awaits further study. Alternatively, to eliminate the load dependency and geometrical effect on the end-systolic parameters (chamber physiology), it might be better to define myocardial tissue contractile properties, such as end-systolic stiffness, by transforming the P-V relationship into the stress-strain relationship (3, 15).| |
ACKNOWLEDGEMENTS |
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We thank John I. Thornby, a biostatistician at Baylor College of Medicine, for statistical review of this manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Nemoto, 2002 Holcombe Blvd., Bldg. 110, Rm. 151C, Houston, TX 77030 (E-mail: snemoto{at}bcm.tmc.edu) and B. A. Carabello, Houston Veterans Affairs Medical Center, 2002 Holcombe Blvd., Houston, TX 77030 (E-mail: blaseanthony.carabello{at}med.va.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00765.2001
Received 4 September 2001; accepted in final form 25 July 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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