Download Stroke volume-to-wall stress ratio as a load

J Appl Physiol 113: 1267–1284, 2012.
First published August 23, 2012; doi:10.1152/japplphysiol.00785.2012.
Stroke volume-to-wall stress ratio as a load-adjusted and stiffness-adjusted
indicator of ventricular systolic performance in chronic loading
Elie R. Chemaly,1 Antoine H. Chaanine,1 Susumu Sakata,2 and Roger J. Hajjar1
1
Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York; and 2Division of Health Science,
Graduate School of Kio University, Nara, Japan
Submitted 25 June 2012; accepted in final form 21 August 2012
pressure overload; volume overload; stiffness; contractility; wall
stress
LOAD DEPENDENCE HAS LONG BEEN recognized in crude indicators
of cardiac performance, such as stroke volume (SV) and
ventricular pressures, based on the Starling principle, leading
to the development of characteristic plots of load and crude
performance (31, 50). The most popular of such characteristics are the end-systolic pressure-volume (P-V) relationship
(ESPVR) and the relationship between stroke work (SW) and
end-diastolic volume (EDV), or preload-recruitable SW (PRSW)
(31). When fitted linearly, ESPVR is characterized by its slope
Ees (end-systolic elastance) and its volume intercept Vo.
In the last 3 decades, starting shortly after these indicators
were developed, a number of acute and chronic studies have
Address for reprint requests and other correspondence: R. J. Hajjar, Professor and Director, Cardiovascular Research Center, Mount Sinai School of
Medicine, One Gustave L. Levy Place, Box 1030, New York, NY, 10029
(e-mail: [email protected]).
http://www.jappl.org
questioned the ability of these load-adjusted indicators to
accurately reflect systolic performance.
Baan and Van der Velde (3) have shown in an acute study,
that Ees increased in response to increased afterload more than
with increased preload, while Sodums et al. (43) observed a
leftward shift of the ESPVR intercept (decreased Vo) in response to acutely increased afterload. Another report by Little
et al. (31) studied ESPVR, PRSW, and the maximum change in
pressure over time (dP/dtmax)-EDV characteristic with acute
inotropic and vasoconstrictive interventions and found only
ESPVR to be afterload dependent, through a leftward shift.
More recently, Blaudszun and Morel (5) performed an acute
study of P-V analysis in rats treated with several positive and
negative inotropes, vasoconstrictors, and vasodilators and suggested that Ees was afterload dependent and did not reflect
inotropy, as opposed to its intercept Vo. Van den Bergh et al.
(50) acutely studied the inotropic response and response to
changes in preload and afterload of several load-adjusted
indicators in normal mice and concluded PRSW to be the most
useful indicator, based on inotropic response and load dependence. Another limitation of these indicators was shown in a
relatively recent report from Aghajani et al. (2). They studied
ESPVR and PRSW in large-animal models of acute heart
failure from various causes and found Ees to be increased in
acute heart failure, reflecting the preload dependence of the
failing hearts and thus contradicting the reduced systolic function; PRSW responded variably in these experiments (2).
Ees measures left ventricular (LV) systolic performance (7,
10), as well as ventricular stiffness. The increase of Ees in
processes affecting ventricular stiffness is well recognized in
recent and less recent reports. Two such processes (7) are aging
(14) and hypertension (8). In human hypertensive heart disease, Borlaug et al. (8) have recently shown that increases in
arterial elastance (Ea) were matched by increases in Ees with
preserved Ees-to-Ea ratio (Ees/Ea) and coupling. The increase
in Ees was maintained in hypertensive patients with heart
failure and preserved LV ejection fraction (LVEF), while other
indicators showed reduced contractility (8). Thus a complex
interplay between ventricular systolic stiffness and afterload
confounds the relationship between ventricular contractility
and Ees, in acute and chronic settings. In addition, Zile et al.
(52) showed a lack of response to the ex vivo maximum
systolic elastance of the LV to ischemia-reperfusion when
ischemia-reperfusion also led to an increase in LV end-diastolic pressure (LVEDP). Altogether, the findings by Zile et al.
(52) and others (8) demonstrate a significant interference of LV
passive stiffness and afterload in the value of Ees to assess LV
contractility.
Other known load-independent variables, such as PRSW,
may also remain elevated, or at least not lowered, in pres-
8750-7587/12 Copyright © 2012 the American Physiological Society
1267
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Chemaly ER, Chaanine AH, Sakata S, Hajjar RJ. Stroke
volume-to-wall stress ratio as a load-adjusted and stiffness-adjusted indicator of ventricular systolic performance in chronic
loading. J Appl Physiol 113: 1267–1284, 2012. First published
August 23, 2012; doi:10.1152/japplphysiol.00785.2012.—Loadadjusted measures of left ventricle (LV) systolic performance are
limited by dependence on LV stiffness and afterload. To our knowledge, no stiffness-adjusted and afterload-adjusted indicator was tested
in models of pressure (POH) and volume overload hypertrophy
(VOH). We hypothesized that wall stress reflects changes in loading,
incorporating chamber stiffness and afterload; therefore, stroke volume-to-wall stress ratio more accurately reflects systolic performance.
We used rat models of POH (ascending aortic banding) and VOH
(aorto-cava shunt). Animals underwent echocardiography and pressure-volume analysis at baseline and dobutamine challenge. We
achieved extreme bidirectional alterations in LV systolic performance,
end-systolic elastance (Ees), passive stiffness, and arterial elastance
(Ea). In POH with LV dilatation and failure, some load-independent
indicators of systolic performance remained elevated compared with
controls, while some others failed to decrease with wide variability. In
VOH, most, but not all indicators, including LV ejection fraction,
were significantly reduced compared with controls, despite hyperdynamic circulation, lack of heart failure, and preserved contractile
reserve. We related systolic performance to Ees adjusted for Ea and
LV passive stiffness in multivariate models. Calculated residual Ees
was not reduced in POH with heart failure and was reduced in VOH,
while it positively correlated to dobutamine dose. Conversely, stroke
volume-to-wall stress ratio was normal in compensated POH, markedly decreased in POH with heart failure, and, in contrast with LV
ejection fraction, normal in VOH. Our results support stroke volumeto-wall stress ratio as a load-adjusted and stiffness-adjusted indicator
of systolic function in models of POH and VOH.
1268
Ventricular Stiffness and Performance in Chronic Loading
sure overload-induced LV systolic dysfunction, as shown
recently (12).
We took a systematic approach to test two major hypotheses.
1) The first hypothesis is as follows. Most classical indicators of load-independent systolic performance are affected by
acute and chronic changes of LV stiffness and afterload. This
effect precludes their use as indicators of LV systolic performance when LV stiffness and afterload either increase or
decrease in chronic loading. Therefore, a load-adjusted and
stiffness-adjusted indicator is needed.
2) The second hypothesis is as follows. The ratio of SV to
wall stress (SV/wall stress) can serve as a load-adjusted and
stiffness-adjusted indicator of LV systolic performance.
To test our hypotheses, we varied LV systolic performance,
along with Ees, Ea, and LV passive stiffness over a wide range
in rat models of pressure-overload hypertrophy (POH) and
volume-overload hypertrophy (VOH), and measured baseline
and postdobutamine LV function and stiffness.
Animal Use and Care
All animals were obtained and handled, as approved by the Institutional Animal Care and Use Committee of the Mount Sinai School
of Medicine, in accordance with the “Principles of Laboratory Animal
Care by the National Society for Medical research and the Guide for
the Care and Use of Laboratory Animals” (National Institutes of
Health Publication no. 86 –23, revised 1996).
Animal models used and their time points are shown in Table 1.
Surgical Model of Pressure-Overload-Induced LV Hypertrophy and
Failure by Ascending Aortic Banding
The surgical procedure was previously described (33). Male
Sprague-Dawley rats (body weight 70 –100 g) underwent ascending
aortic constriction under general anesthesia (ketamine up to 85 mg/kg
and xylazine up to 10 mg/kg, intraperitoneally). The chest was shaved,
and animals were intubated and mechanically ventilated. The chest area
was scrubbed and opened intercostally on the right side within 1 cm of
the axilla to access the ascending aorta. The ascending aorta was
identified and separated from the superior vena cava by blunt dissection. A Weck hemoclip (Teflex medical) stainless-steel clip of ⬃1 mm
of adjusted diameter was placed around the ascending aorta. The chest
was closed in three layers, and animals were allowed to recover.
Sham-operated animals underwent the same procedure without aortic
constriction. Normal animals were virgin male Sprague-Dawley rats
purchased at an approximate age of 6 mo and an approximate body
weight of 500 g.
Surgical Model of Volume-Overload-Induced LV Hypertrophy by
Aorta-Cava Fistula
The surgical procedure was described elsewhere (49). Male
Sprague-Dawley rats (body weight 250 –300 g) underwent aorta-cava
fistula creation under general anesthesia (ketamine up to 85 mg/kg and
xylazine up to 10 mg/kg, intraperitoneally). The abdominal area was
shaved, and animals were intubated and mechanically ventilated.
Chemaly ER et al.
Ventral laparotomy was performed. The aorta and inferior vena cava
(IVC) were exposed between the renal arteries and the iliac bifurcation. Both vessels were temporarily occluded at two sites, proximal
and distal to the intended shunt site, with a Bulldog clip. An 18GA
angiocath was inserted over a needle into the exposed free wall of the
abdominal aorta and advanced through the connective tissue fascia
separating the aorta and the IVC. Several back-and-forth insertions
and withdrawals of the angiocath were performed across the two
vessels through the same hole to ensure the presence of a significant
shunt. After the needle and the angiocath were withdrawn, the ventral
aortic puncture site was sealed with a drop of cyanoacrylate. Successful shunt could be confirmed by pulsatile flow of oxygenated blood
into the vena cava from the aorta. Laparotomy was closed in two
layers, and animals were allowed to recover. In sham animals, the
laparotomy was performed without functional shunt.
Echocardiographic and Morphometric Assessment of LV Geometry
and Function
Echocardiography was performed at designated time points under
sedation by intraperitoneal ketamine up to 80 mg/kg, with starting
doses as low as 10 mg given to diseased rats and supplemented by
additional injections until optimal sedation was obtained. Sedation
was optimized by giving the lowest dose of ketamine needed to
1) restrain the animal and prevent motion artifact, and 2) maintain the
heart rate in the range of 350 – 450 beats/min.
Ketamine was chosen based on our laboratory’s previous experience (12–14) and considering that alternative agents had either a long
duration of action (pentobarbital), potentially unsafe for heart failure
animals, or a bradycardic effect (isoflurane, xylazine), as demonstrated elsewhere (44). Moreover, ketamine is recommended in murine echocardiography based on a favorable comparison against ketamine/xylazine (51).
The chest was shaved. Short-axis parasternal two-dimensional
views of the LV at the midpapillary level and long-axis parasternal
views of the LV were obtained using a GE Vivid echocardiography
apparatus with a 13- to 14-MHz linear array probe (General Electric,
New York, NY). M-mode measurements of the size of the LV walls
and cavities were obtained by two-dimensional guidance from the
short-axis view of the LV, as recommended by the American Society
of Echocardiography (29). Volumes of the LV cavity in end-diastole
and end-systole were calculated using an area-length formula, where
the LV is assumed to be bullet-shaped, as previously recommended
and described (13, 23, 29). LV EDV and end-systolic volume (ESV)
were thus calculated as follows: V ⫽ 5/6 ⫻ A ⫻ L, where V is the
volume of the LV cavity in ml, A is the cross-sectional area of the LV
cavity in cm2 obtained from a parasternal short-axis image at the midpapillary level, and L is the length of the LV cavity measured as the
distance from the endocardial LV apex to the mitral-aortic junction on the
parasternal long-axis image, as previously described (13, 23).
Morphometric analysis consisted in separately weighing the left
and right ventricles (RV) at the time of death.
Animal Selection and Group Assignment Based on
Echocardiographic Analysis in Pressure Overload
Echocardiography performed at 2 mo after aortic constriction
distinguished animals with either compensated concentric LV hypertrophy (CLVH) or dilated cardiomyopathy (DCM).
Table 1. Time points of postoperative data collection for the animal models used in the study
Group
Surgery
Pressure overload hypertrophy
Mild pressure overload hypertrophy
Volume overload hypertrophy 3 mo
Ascending aortic banding
Ascending aortic banding
Aorta-caval shunt
Intermediate Echocardiography Time
(data not shown)
2, 3 mo
2–4 mo
1 wk/1 mo on selected animals
J Appl Physiol • doi:10.1152/japplphysiol.00785.2012 • www.jappl.org
Terminal Echocardiography and
Hemodynamics Time
4 mo
6 mo
3 mo
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METHODS
•
Ventricular Stiffness and Performance in Chronic Loading
Based on the observation that a subset of rats with POH undergo
LV dilatation, with end-diastolic dimensions reaching or exceeding
the numbers observed with volume-overload rats, we developed
criteria for DCM in rats after pressure overload. The three proposed
criteria of LV measurement are EDV ⬎ 750 ␮l, ESV ⬎ 200 ␮l, and
LVEF ⬍ 70%. At least two, and usually three, of the criteria must be
met, with echocardiography performed on ketamine conscious sedation with a heart rate of 350 to 450 beats/min.
Animals with confirmed DCM received an echocardiography at 3
and 4 mo and were killed thereafter. Animals with CLVH at 2 mo
received an additional echocardiography at 4 mo and were killed if
still in CLVH or followed for 2 additional mo if they had transitioned
to DCM. At the beginning of the study, longer time frames were used
based on previous reports (42, 45). Rats in CLVH at 4 mo were
followed until 6 mo and made an additional separate group (CLVH 6
mo, mild POH) that was found to have milder POH.
•
Integrating Ees and Vo in One Parameter
To further integrate simultaneous changes in Ees and Vo, we used
an approach similar to Crottogini et al. (17). We sought to combine
changes in Ees and changes in Vo in one variable. Knowing that either
an increase in Ees or a decrease in Vo will increase the area inside the
triangle delimited by ESPVR, the horizontal (volume) axis and a
vertical line passing through a reference volume (Vr) were used to
compare different conditions. The area under this triangle is an
integration of ESPVR (Fig. 1):
Vr
Integrated共ESPVR,Vo, Vr兲 ⫽
Rats were anesthetized with inhaled 5% (volume/volume) isoflurane for induction, intubated, and mechanically ventilated.
Isoflurane was chosen based on our experience (12, 13), on existing
methodological recommendations (37), and considering the possibility of dosing adjustment. Isoflurane was progressively lowered to
1.5–2% (volume/volume) for surgical incisions. The chest was opened
through a median sternotomy. A 1.9F rat P-V catheter (Scisense,
London, Ontario, Canada) was inserted into the LV apex through an
apical stab performed with a 25GA needle. Hemodynamic recordings
were performed after 5 min of stable heart rate. Isoflurane was
maintained at 0.75–1% for adequate anesthesia and a stable heart rate
in the range of 300 –350 beats/min. Hemodynamics were recorded
subsequently through a Scisense Advantage P-V Control Unit (FY897B).
The intrathoracic IVC was transiently occluded to vary venous return
during the recording to obtain load-adjusted P-V relationships (see
Fig. 5, RESULTS). Linear fits were obtained for ESPVR, PRSW, and the
end-diastolic P-V relationships (EDPVR). Fifty microliters of 30%
NaCl were slowly injected into the external jugular vein for ventricular parallel conductance measurement, as previously described (37).
Blood volume was obtained as blood conductance and calibrated
based on Baan’s equation (4) using the baseline SV by conductance
and matching it with the SV obtained by echocardiography, as
previously described (37). In all P-V tracings, the end-systolic pressure (ESP) and ESV were determined at the end of the systolic
ejection phase.
(2)
Using a linear ESPVR fit, Eqs. 1 and 2 are combined
Ees
Integrated共ESPVR,Vo, Vr兲 ⫽
2
⫻ 共Vr2 ⫺ V2o兲
⫺ Ees ⫻ Vo ⫻ 共Vr ⫺ Vo兲
(3)
Other P-V Loop Parameters
The Ea was calculated as the ratio of ESP to SV. SW (in mmHg ⫻
␮l) was obtained from the area of the P-V loop representing LV
ejection. PRSW (in mmHg) is the slope of SW vs. EDV (␮l) when
EDV is varied by IVC occlusion (37).
Meridional LV wall stress ␴ was calculated as reported by Grossman et al. (22) as
␴⫽
PR
2h共1 ⫹ h ⁄ 2R兲
(4)
where P is LV pressure, R is LV cavity radius, and h is LV wall
thickness, measured at corresponding points of the cardiac cycle
(end-systole or end-diastole).
Dobutamine Challenge During P-V Loop Acquisition
Dobutamine was infused through the external jugular vein, first at
8 ␮g/min for 1–2 min for priming, then at 1, 2, 4, and 8 ␮g/min.
Infusion was maintained for 5 min at each level before P-V loop data
Pressures at Equal Volumes From the Linear ESPVR
It is recognized that either an increase in Ees or a decrease in Vo
leads to a shifting of ESPVR to higher pressures at equal volumes
(10). Thus, to align different animals on the same volumes, and
calculate ESP at equal ESV, as previously reported (13), we used the
linear ESPVR equation:
ESP ⫽ Ees ⫻ 共ESV ⫺ Vo兲
(1)
Fig. 1. Integrating the end-systolic pressure (ESP)-volume (ESV) relationship
between the volume intercept Vo and a reference volume Vr, based on
Crottogini et al.(17).
J Appl Physiol • doi:10.1152/japplphysiol.00785.2012 • www.jappl.org
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Invasive Hemodynamic Measurements by P-V Loops
兰 ESP ⫻ d共ESV兲
Vo
Animal Selection and Group Assignment Based on
Echocardiographic Analysis in Volume Overload
Successful patent aorta-cava shunt was determined by an enddiastolic LV diameter by M-mode echocardiography of at least 8 mm,
and usually more than 9 mm in the same conditions of sedation
described above, at echocardiography completed 1 mo after surgery.
Moreover, all animals with patent fistulas had continuous and turbulent shunt flow measured by pulse-wave and color-flow Doppler
ultrasound, in addition to a distinct palpable abdominal thrill. The
fistula itself was thus detected as early as 1 wk after surgery. Animals
were analyzed 3 mo postshunt (Table 1).
1269
Chemaly ER et al.
1270
Ventricular Stiffness and Performance in Chronic Loading
collection. In normal or sham-operated rats, the full infusion protocol
was often not completed due to a very low ESV achieved on
dobutamine, interfering with the measurement catheter, as previously
reported (50).
Statistical Analysis
RESULTS
Ventricular Hypertrophy and Dysfunction by
Echocardiographic and Morphometric Analysis
Echocardiographic and morphometric characteristics are
shown in Table 2.
In POH, LV wall thickness increased significantly, with
concentric hypertrophy in CLVH and LV dilatation (significant
increases in EDV and ESV) with decreased LVEF in heart
failure (DCM group). Interestingly, LV wall thickness was
significantly lower in the DCM group than in their CLVH
counterpart (Table 2, top). In all POH, LV mass increased
significantly, with a further increase in LV/body weight in
DCM vs. CLVH counterpart (Table 2, top), while in DCM, RV
mass was also increased, reflecting POH of the RV from
increased LV filling pressures (Tables 2, top, and 3, top).
Similarly, a mild increase in RV mass did reach statistical
significance in severe POH with CLVH vs. normal (uncorrected P value); however, the RV weight-to-body weight ratio
did not differ (Table 2, top); this finding is also in line with a
milder increase in LV filling pressures in CLVH (Table 3, top).
Mild POH animals had significantly lower EDV and ESV
and significantly higher LVEF than did sham counterparts
(Table 2, middle).
VOH was eccentric (significant increases in EDV and ESV),
with significant increase in SV and reduction in LVEF and
increased LV and RV masses, reflecting biventricular volume
overload (Table 2). Comparable LV mass was reached with
POH (either CLVH or DCM, Table 2, top) and VOH (Table 2,
bottom).
Chemaly ER et al.
Body Weight
Body weights of different animal groups are presented in
Table 2. DCM animals had a significantly lower body weight
than sham counterparts, reflecting clinical heart failure (Table
2, top). The higher body weight in CLVH vs. normal animals
in Table 2, top, is design related (see METHODS). Body weight
was also significantly lower in the group of mild POH followed
for 6 mo compared with sham (Table 2, middle); the explanation of this finding is less clear since long-term aortic constriction can impact animal growth, and slower growth may improve tolerance to chronic constriction. Volume overload rats 3
mo after aorta-caval fistula had a significantly higher body
weight than sham (Table 2, bottom); this may reflect extracellular fluid retention.
Baseline Heart Rate by Echocardiography
and Invasive Hemodynamics
Heart rate measured during echocardiography was significantly lower in DCM compared with CLVH and control animals
(11% relative change, Table 2, top). Heart rate during invasive
hemodynamic measurements was significantly lower in DCM
compared with normal animals (11% relative change, Table 3,
top), and in shunt 3-mo animals compared with sham 3-mo
counterparts (9% relative change, Table 3, bottom).
Baseline Steady-State LV Pressure Patterns
Baseline (without dobutamine challenge) steady-state (no
IVC occlusion) hemodynamics are shown in Table 3. Significant increases in LV maximal pressure were observed in all
POH animals, with comparable increase between CLVH and
DCM in severe POH (Table 3, top). In the mild POH-CLVH
group, maximal LV pressure shown in Table 3, middle, was
also significantly lower than in CLVH and DCM from severe
POH (Table 3, top). LV ESP was significantly increased
compared with sham in severe, but not mild, POH (Table 3, top
and middle). LVEDP was significantly increased in DCM,
compared with controls and CLVH (Table 3, top). CLVH
showed a milder elevation of LVEDP, which was significant
compared with normal rats (uncorrected P ⬍ 0.002, Table 3,
top).
The LV dP/dtmax differed between POH and controls (P ⫽
0.037 by ANOVA in Table 3, top, highest in CLVH and lowest
in sham), likely reflecting the preload and afterload dependence of LV dP/dtmax (26, 32). The ␶ constant of isovolumic
relaxation was highest in the DCM group of POH, indicating
impaired relaxation (Table 3, top, P ⫽ 0.002 by ANOVA).
Effect of Dobutamine on Steady-State Hemodynamics
Reveals Differential Response Between Models
Animals from all groups were subjected to increasing rates
of dobutamine infusions (see METHODS). Figures 2– 4 show the
dobutamine dose-response of basic hemodynamic parameters.
LV peak pressure was either reduced or unchanged by dobutamine, reflecting concurrent vasodilator and positive inotropic
effects (Fig. 2). Dobutamine-associated reductions in maximal
LV pressure were mostly seen in control animals (Fig. 2). The
effect of dobutamine on LV maximal pressure was variable
between control groups (Fig. 2), likely reflecting differences in
baseline vascular resistance, endothelial function, age, and anes-
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Continuous variables were compared by ANOVA, followed by
post hoc pairwise comparisons using Student’s t-test with Bonferroni
correction for multiple testing. The statistical power of the Bonferroni
test is reduced when the number of comparisons increases; therefore,
experimental animals were compared with their own controls within
substudies to avoid irrelevant comparisons. Considering the important
risk of type 2 error related to the Bonferroni correction (38), we
provided all of the Bonferroni-corrected P values and, in addition, the
uncorrected P values when those were significant. Multivariate
ANOVA was used in selected comparisons.
A multiple repeated-measurement ANOVA was used for dobutamine dose-response measurements, with an interaction term between
dobutamine dose and animal group. The P values after repeatedmeasurement ANOVA were reported after corrections for lack of
sphericity, using the Huynh-Feldt correction.
Simple and multiple linear regression was used, when indicated. A
P value of 0.05 was set as a threshold for significance.
Graphic representation of data in box plots shows the median value
flanked by the 25th and 75th percentiles as edges of the box, with bars
representing the adjacent values to the 25th and 75th percentiles, and
dots representing additional outlying values.
Statistical analysis used the Stata version 10.1 software (Stata,
College Station, TX).
•
620
57
27
0.005
560
62
13
406
44
26
0.43
417
35
13
407
31
8
0.96
408
47
6
ESV, ␮l
SV, ␮l
EF, %
LV Anteroseptum
(Diastole), mm
448
81
11
465
66
8
0.36
0.57
1.00
466
100
19
1.00
413
91
14
1.00
1.00
87.04
4.50
11
81.68
6.23
8
⬍0.001
⬍0.001
⬍0.001
53.47
14.96
19
⬍0.001
86.07
7.03
14
1.00
1.00
2.1
0.2
11
2.1
0.2
8
⬍0.001
0.001
⬍0.001
2.8
0.3
19
⬍0.001
3.2
0.4
14
⬍0.001
⬍0.001
1117
288
26
⬍0.001
455
72
12
465
99
8
0.02
615
110
7
400
82
8
0.08
480
81
7
86.33
3.57
8
0.001
78.23
3.23
7
348
131
26
⬍0.001
69
23
12
769
193
26
⬍0.001
386
58
12
69.19
6.46
26
⬍0.001
85.02
3.65
12
Volume-overload hypertrophy 3 mo
64
25
8
0.001
135
34
7
2.1
0.2
26
0.99
2.1
0.2
13
3.4
0.4
8
⬍0.001
2.2
0.1
7
Mild pressure overload hypertrophy (aortic banding 6 mo)
68
31
11
107
43
8
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
516
101
11
572
85
8
⬍0.001
440
224
19
⬍0.001
72
51
14
1.00
1.00
906
209
19
⬍0.001
484
120
14
1.00
1.00
Pressure overload hypertrophy (aortic banding 4 mo)
EDV, ␮l
3.40
0.45
19
⬍0.001
0.007
⬍0.001
2.09
0.13
11
1.80
0.16
8
⬍0.001
2.81
0.35
8
⬍0.001
1.72
0.14
8
2.90
0.42
21
⬍0.001
1.82
0.21
9
0.20
⬍0.001
1.08
0.08
11
1.15
0.12
8
⬍0.001
1.61
0.29
8
0.001
1.14
0.10
8
1.81
0.32
21
⬍0.001
1.05
0.07
9
2.99
0.35
14
⬍0.001
⬍0.001
LVW/BW,
mg/g
1.87
0.22
19
⬍0.001
1.73
0.18
14
⬍0.001
⬍0.001
LV Mass, g
0.50
0.10
21
⬍0.001
0.27
0.03
9
0.28
0.10
8
0.85
0.29
0.03
8
0.79
0.13
21
⬍0.001
0.46
0.06
9
0.49
0.17
8
0.31
0.44
0.04
8
0.48
0.07
11
0.45
0.08
8
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
0.25
0.03
11
0.28
0.03
8
⬍0.001
0.97
0.15
19
⬍0.001
0.53
0.16
14
0.85
1.00
RVW/BW,
mg/g
0.31
0.08
14
1.00
0.19 (0.034
uncorrected)
0.53
0.08
19
⬍0.001
RV Mass, g
n, No. of animals. EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume; EF, ejection fraction; LV, left ventricle; LVW/BW, mg/g: ratio of LV weight in mg over body weight in g;
RV, right ventricle; RVW/BW, mg/g: ratio of RV weight in mg over body weight in g; CLVH, compensated-concentric left ventricular hypertrophy; DCM, dilated cardiomyopathy; ANOVA, analysis of
variance.
Sham-3 mo
Mean
SD
n
P vs. sham
Mean
SD
n
572
44
8
0.001
662
47
8
367
46
19
0.36 (0.026
uncorrected)
0.03
0.12 (0.047
uncorrected)
399
32
11
412
46
8
0.017
413
50
14
1.00
1.00
Heart Rate,
beats/min
Chemaly ER et al.
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Shunt-3 mo
Mean
SD
n
P vs. sham
Mean
SD
n
Mean
SD
n
Mean
SD
n
P for ANOVA
521
54
11
644
109
8
0.001
1.00
1.00
P vs. CLVH
P vs. normal
Mean
SD
n
P vs. sham
583
49
14
0.19
0.10 (0.007
uncorrected)
553
47
19
0.01
Body Weight, g
Mean
SD
n
P vs. sham
P vs. normal
Parameter
•
Sham-6 mo
CLVH
Sham-4 mo
Normal
DCM
CLVH
Group
Table 2. Echocardiographic and morphometric analysis of animal models used in the study
Ventricular Stiffness and Performance in Chronic Loading
1271
1272
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
Table 3. Baseline invasive hemodynamic analysis of animal models used in the study
Group
Parameter
LV Maximal
Pressure, mmHg
LV End-diastolic
Pressure, mmHg
LV End-systolic
Pressure, mmHg
LV Maximal dP/dt,
mmHg/s
␶ of Isovolumic LV
Relaxation (Weiss)
Heart Rate,
beats/min
10.35
2.53
7
1.00
342
19
7
1.00
1.00
1.00
Pressure overload hypertrophy (aortic banding 4 mo)
CLVH
DCM
245
26
7
⬍0.001
13
4
7
1.00
P vs. normal
⬍0.001
Mean
SD
n
P vs. sham
261
29
17
⬍0.001
0.30 (0.002
uncorrected)
27
7
17
⬍0.001
177
26
17
⬍0.001
0.84
⬍0.001
1.00
⬍0.001
140
10
8
133
8
5
⬍0.0001
⬍0.001
7
2
8
9
1
5
⬍0.0001
⬍0.001
132
13
8
122
13
5
⬍0.0001
P vs. CLVH
Normal
Sham-4 mo
P vs. normal
Mean
SD
n
Mean
SD
n
P for ANOVA
166
29
7
0.017
0.045
9758
1095
7
0.07 (0.004
uncorrected)
0.26 (0.006
uncorrected)
9199
1719
17
0.19
1.00
0.76
8304
590
8
7680
667
5
0.037
12.45
2.05
17
0.13 (0.028
uncorrected)
0.10 (0.044
uncorrected)
0.002
9.29
0.85
8
10.18
1.00
5
0.002
317
33
17
1.00
0.36
0.019
356
21
8
330
34
5
0.020
Mild pressure overload hypertrophy (aortic banding 6 mo)
CLVH
Sham-6 mo
Mean
SD
n
P vs. sham
Mean
SD
n
199
8
4
0.002
130
25
4
Mean
SD
n
P vs. sham
Mean
SD
n
128
8
14
0.14
134
9
5
12
8
4
0.15
5
1
4
149
12
4
0.15
120
34
4
8555
678
4
0.30
7621
1500
4
9.24
0.57
4
0.42
8.95
0.36
4
355
37
4
0.43
334
32
4
8535
705
14
0.97
8547
471
5
10.39
1.75
14
0.16
9.13
1.31
5
348
32
14
0.042
381
18
5
Volume-overload hypertrophy 3 mo
Shunt-3 mo
Sham-3 mo
9
3
14
0.10
7
2
5
111
17
14
0.08
126
9
5
n, No. of animals. dP/dt, change in pressure over time; ␶, time constant.
thesia-related effects. dP/dtmax increased in response to dobutamine, with significantly impaired response in POH (Fig. 3A),
preserved response in mild POH (Fig. 3B), and preserved to
enhanced response in VOH (statistically significant group-dose
interaction, Fig. 3C). Stroke volume response to dobutamine was
significantly reduced in POH and mild POH (Fig. 4, A and B) and
preserved in VOH (Fig. 4C).
P-V Loops During IVC Occlusion
The baseline Vo intercept of ESPVR was significantly
higher in DCM after POH, with P ⬍ 0.0001 by ANOVA and
P ⱕ 0.001 for DCM compared with normal, sham counterparts and CLVH counterparts (Table 4, top). The baseline Vo intercept did not differ significantly from control
animals in other disease groups (Table 4). POH was associated with a significant increase in the slope of EDPVR
(Fig. 7A).
Serial P-V loops after IVC occlusion are shown in Fig. 5, in
representative POH and VOH animals.
Dobutamine Challenge: Effect on Ees, Ea,
and EDPVR
Baseline Ees, Ea, Vo, Ees/Ea, and EDPVR in POH
and VOH
In responsive animals, dobutamine marginally increased Ees
(Fig. 8, B and C), despite a major and significant decrease in Ea
(Fig. 8), resulting in large and significant increases in the
Ees/Ea with an “uncoupling” of the Ees-Ea coupling observed
at baseline (Fig. 8). The response of Ea and Ees/Ea was
significantly reduced in all disease models, except mild POH
(Fig. 8). Dobutamine did not lead to appreciable changes in
EDPVR (data not shown).
Baseline (without dobutamine challenge) Ees, Ea, Ees/Ea, and
EDPVR were obtained during IVC occlusion.
Baseline Ees and Ea were the highest in POH and the lowest
at 3 mo of VOH (Fig. 6). Baseline Ees/Ea was not significantly
affected by POH and significantly reduced in VOH (Fig. 6).
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Mean
SD
n
P vs. sham
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
1273
Fig. 2. Box plots of maximal left ventricular (LV) pressure on dobutamine in animal models of pressure overload hypertrophy (POH) and volume overload
hypertrophy (VOH). LV maximal pressure is stable or reduced by dobutamine infusion in control animals. Dobutamine is infused at 0, 1, 2, 4, and 8 ␮g/ min.
P values for repeated-measurement ANOVA indicate level of significance for group (G), dobutamine dose (D), and group-dose (GD) interaction; P values are
omitted for nonsignificant results. A: POH. P ⬍ 0.0001 for G, P ⫽ 0.045 for D (Huynh-Feldt correction). B: mild POH. P ⫽ 0.0001 for G. C: VOH 3 mo.
P ⫽ 0.0043 for G, P ⫽ 0.01 for D (Huynh-Feldt correction), P ⫽ 0.005 for GD interaction (Huynh-Feldt correction). CLVH, compensated-concentric LV
hypertrophy; DCM, dilated cardiomyopathy. In all figures, *P ⬍ 0.05, **P ⱕ 0.01, ***P ⱕ 0.001, ****P ⱕ 0.0001.
The pertinence of these findings in load-adjusted indicators
of systolic performance to our main hypothesis is further
discussed.
Table 4 presents baseline values of three load-adjusted
indicators of LV systolic performance: PRSW, ESP at a
reference ESV of 800 ␮l by conductance (based on Eq. 1),
and the ESPVR integrated between Vo and 800 ␮l (based on
Eqs. 2 and 3).
All three indicators showed high variability in diseased
groups and were significantly and consistently elevated in
CLVH animals compared with controls (Table 4, top and
middle).
DCM animals had consistently lower values than CLVH
animals (Table 4, top) for all three parameters. PRSW was
higher in DCM than controls (Table 4, top, significant uncorrected P values). ESP measured at an ESV of 800 ␮l by
conductance was lower in DCM than controls, but this difference did not reach statistical significance (Table 4, top). The
integrated ESPVR from Vo to 800 ␮l by conductance was
significantly lower in DCM than in controls (Table 4, top).
In contrast, VOH animals had lower ESP at an ESV of 800
␮l by conductance than sham counterparts; however, they did
not differ from controls by the two other indicators, PRSW and
integrated ESPVR from Vo to 800 ␮l by conductance (Table 4,
bottom).
Residual Ees Adjusted on Ea and EDPVR and Its
Connection to Systolic Performance
To address the confounding effect of Ea and EDPVR on the
relationship between Ees and systolic performance, we calculated a residual value of Ees after adjusting for Ea and EDPVR
in multivariate analysis. We tested the hypothesis that 1) a
reduction in residual Ees would identify systolic failure in
DCM animals; and 2) residual Ees would, conversely, be
relatively preserved in VOH animals showing no heart failure,
mostly preserved response to dobutamine and simultaneous
reductions of Ees, Ea, and EDPVR.
Baseline Ees as a function of Ea and EDPVR. As shown in
Figs. 6 and 7, we have varied Ea from 0.07 to 0.54 mmHg/␮l
and EDPVR from 0 to 0.13 mmHg/␮l in our chronic loading
models, resulting in Ees varying from 0.04 to 0.93 mmHg/␮l.
This severalfold variation of all three parameters allows us to
measure statistical interactions and infer potential mechanical
interactions.
At baseline, and across models, Ees was linearly and significantly correlated to Ea (Fig. 9A) and to the slope of EDPVR
(Fig. 9B).
Fig. 3. Box plots of LV dP/dt max on dobutamine in animal models of POH and VOH. Maximal dP/dt increased in response to dobutamine, with impaired
response in POH, preserved response in mild POH, and enhanced response in VOH. A: POH. P ⫽ 0.003 for G, P ⬍ 0.0001 for D (Huynh-Feldt correction),
P ⫽ 0.0006 for GD interactions (Huynh-Feldt correction). B: mild POH. P ⫽ 0.01 for G, P ⫽ 0.004 for D (Huynh-Feldt correction). C: VOH 3 mo. P ⬍ 0.0001
for D (Huynh-Feldt correction), P ⫽ 0.037 for GD interaction (Huynh-Feldt correction). P values are for repeated-measurements ANOVA.
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Other Load-Adjusted Indicators of LV Systolic Performance
at Baseline Are Variably Dependent on LV Afterload
and Stiffness
1274
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
Fig. 4. Box plots of stroke volume (SV) (by conductance) on dobutamine in animal models of POH and VOH. SV response to dobutamine is blunted in POH
groups, reduced in mild POH, and preserved to marginally enhanced in VOH. A: POH. P ⬍ 0.0001 for G, P ⬍ 0.0001 for D and GD interaction (Huynh-Feldt
correction). B: mild POH. P ⫽ 0.0004 for G, P ⫽ 0.0003 for D (Huynh-Feldt correction), P ⫽ 0.016 for GD interaction (Huynh-Feldt correction). C: VOH 3
mo. P ⬍ 0.0001 for G, P ⬍ 0.0001 for D (Huynh-Feldt correction), P ⫽ 0.065 for GD interaction (uncorrected). P values are for repeated-measurements
ANOVA.
Ees ⫽ 0.62Ea ⫹ 2.0EDPVR ⫹ 0.0046
(5)
where R2 ⫽ 0.44 for the model, P ⫽ 0.002 for Ea, and P ⫽
0.011 for EDPVR; the intercept did not differ significantly
from zero (P ⫽ 0.92). Thus, when both Ea and LV passive
stiffness are varied chronically over a wide range, they independently and positively influence LV Ees.
Residual Ees in the assessment of LV systolic performance at
baseline in DCM animals after pressure overload. Based on
the statistically independent correlation of Ees to Ea and
EDPVR, we sought to determine the residual variation of Ees
in models of variable (severe or marginal) systolic impairment
after adjusting for Ea and EDPVR. We assessed the ability of
residual Ees to reflect systolic dysfunction independently from
afterload and passive stiffness.
We compared n ⫽ 27 control (normal and sham-operated)
animals to n ⫽ 17 animals with DCM after POH, considering
that these animals had impaired LV systolic performance: LV
dilatation in face of POH, decreased LVEF, and heart failure
(Tables 2 and 3). In univariate analysis, Ees, Ea, and EDPVR
were all significantly higher in DCM than in controls (P ⱕ
0.0001 for Ees and EDPVR, P ⫽ 0.009 for Ea). To calculate
the difference in residual Ees after adjustment on Ea and
EDPVR between DCM and control animals, we used a multiple-linear regression with Ees as a dependent variable, shown
in Table 5. Residual Ees did not decrease and remained
nonsignificantly higher by 0.11 mmHg/␮l in DCM animals
(P ⫽ 0.15, Table 5). Due to the high colinearity between DCM
status, Ea, and EDPVR, all independent variables lost their
statistical significance in the multivariate model. These results
indicate 1) that Ees is highly constrained by LV stiffening in
POH, even POH associated with overt LV systolic failure; and
2) that, in POH with heart failure, residual Ees is not decreased
along with decreased systolic performance.
Residual Ees in the assessment of LV systolic performance at
baseline in chronic volume overload. Animals with chronic
aorta-caval shunt (3 mo) had lower LVEF, lower Ees, and
lower Ea than sham counterparts. However, their filling
pressures did not indicate heart failure, and dobutamine
challenge showed relatively maintained contractile reserve,
in contrast to the similarly dilated POH-DCM animals.
Using the approach outlined in Table 5, we determined the
residual change in Ees associated with aorta-caval shunt at
3 mo (n ⫽ 14 animals) compared with n ⫽ 27 control
animals. As opposed to DCM in POH, Ees, Ea, and EDPVR
were all decreased in shunt animals at 3 mo compared with
controls (P ⬍ 0.0001 for Ees and Ea, P ⫽ 0.003 for
EDPVR). However, the residual Ees associated with volume
overload, adjusted for Ea and EDPVR, was significantly
reduced by 0.06 mmHg/␮l in shunt animals compared with
controls (P ⫽ 0.02, Table 6).
Residual effect of dobutamine, DCM, and VOH on Ees after
adjustment on Ea and EDPVR. To better understand the
interconnection between Ees, Ea, and EDPVR in relationship
with dobutamine dose as a measure of inotropy, the multivariate analyses performed in Tables 5 and 6 were extended to
include Ees adjusted on Ea and EDPVR, dobutamine dose,
systolic dysfunction of variable severity from pressure or
volume overload (disease model variable), and the interaction
between dobutamine dose and disease model. The goal was to
assess the ability of the afterload-adjusted and complianceadjusted Ees to respond to the simultaneous inotrope-vasodilator dobutamine and to distinguish the response in overt heart
failure animals (DCM group) or animals with subtle (or no)
systolic dysfunction (shunt 3 mo group) from the response in
controls.
The multivariate linear regressions are reported in Tables 7 and 8.
Ees, adjusted on Ea and the EDPVR slope, remained higher
than control in DCM and lower than control in shunt. The
adjusted Ees increased independently and significantly with
dobutamine dose, and, using a disease-dose interaction term,
we show a significant blunting of the dobutamine dose response to the adjusted Ees in both disease models (Tables 7 and
8). This result indicates that the residual Ees, although related
to inotropy, does not reliably distinguish the otherwise differ-
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Importantly, the slope of the regression line of Ees vs. Ea
was close to unity, and the intercept of the regression line did
not differ significantly from zero (Fig. 9A), indicating wellpreserved coupling of Ees and Ea across models of chronic
ventricular loading. To test the independent correlation of
EDPVR and Ea to Ees, we used a multiple linear regression,
leading to equation (5)
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
1275
DISCUSSION
Fig. 5. Pressure-volume (P-V) loops after inferior vena cava (IVC) occlusion in
representative pressure and volume overload animals. A: pressure overload animals, with normal (middle loops), CLVH (left loops), and DCM (right loops).
B: volume overload animals, with sham (left loops) and VOH (right loops).
ent inotropic reserve of POH-DCM (blunted) and VOH (preserved), as shown using other indicators (Figs. 3 and 4).
SV/Wall Stress As an Alternative Indicator of Systolic Performance
That Corrects for Ventricular Load and Stiffness
We sought to explain whether the reduced LVEF and the
reduced residual Ees represented truly reduced systolic performance or a feature of remodeling in the otherwise hyperdynamic (high SV, see Table 2) shunt model. We were also
interested in explaining the intriguing increase in ESV and
end-systolic dimensions in the rat aorta-cava shunt model,
shown by us and others (24), considering that increased ESV is
not consistent with diastolic volume overload, nor is it consistent with a low-resistance hyperdynamic circulation (primarily
leading to an increased SV and, logically, to a lower ESV).
To that end, we hypothesized that the increased SV required
by the aorta-cava shunt necessitated an increase in loading
throughout the cardiac cycle, according to the Starling principle (28). We used LV end-diastolic and end-systolic wall stress
as loading indicators (20) and hypothesized that the high
required wall stress would lead to a higher ESV in a more
Our systematic study addresses the chronic afterload and
stiffness dependence of load-adjusted indicators of LV systolic
function using rat models of chronic ventricular loading and
proposes load-adjusted and stiffness-adjusted indicators. LV
systolic performance, afterload, and stiffness were varied in a
bidirectional way over a broad interval using rat models of
pressure and volume overload. Acutely, we used dobutamine
challenge, with distinct inotropic and vasodilator activity.
First, we demonstrate quantitatively the limitations of common and less common load-adjusted indicators of LV systolic
performance, by showing their greater dependence on LV
stiffness and afterload over systolic performance. The latter
was previously shown for Ees in situations of high LV stiffness, such as hypertension (8) and aging (14); we demonstrate
it in the highly compliant ventricles of VOH, where systolic
performance is relatively preserved when assessed comprehensively, and some of the studied indicators markedly reduced.
The comprehensive assessment of systolic failure in the DCM
group takes into account the occurrence of heart failure, LV
dilatation in the face of pressure overload, and the loss of
contractile reserve.
To our knowledge, this is the first study to combine POH,
with or without systolic dysfunction and dilatation, together
with VOH, to study the interplay of chronic changes in LV
stiffness, afterload, and LV systolic performance.
Second, we propose SV/wall stress as a load-adjusted and
stiffness-adjusted indicator of LV systolic performance, and, in
our study, this indicator appears to outperform classical loadadjusted indicators of LV systolic performance.
Previous studies used adjusted indicators, taking into account the slope and intercept of several characteristics (31),
mainly correcting Ees for its intercept Vo (10, 31). We used
classical adjustments of the linearly fitted ESPVR, combining
Ees and Vo, either as pressure at equal volume (13), or by
integration (17), or using the Ees/Ea (11). Our more advanced
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compliant ventricle facing a low afterload (and a low ESP) and
facing a significantly lower ESP at equal ESV compared with
controls (Table 4, bottom). In an approach similar to Gaasch et
al. (20), who measured changes in LV shortening vs. wall
stress, we used the SV/wall stress as another measurement of
load-adjusted systolic performance (Fig. 10). End-systolic and
end-diastolic wall stress were significantly increased in dilated
animals (DCM and shunt groups) compared with controls,
while end-diastolic wall stress was normal in CLVH animals
from severe POH (Table 9); end-systolic wall stress was lower
in CLVH vs. normal (uncorrected P value, Table 9, top). In the
mild POH group as well, end-systolic wall stress was significantly lower than in sham animals (Table 9, middle). DCM
animals had a significantly reduced ratio of SV over enddiastolic and end-systolic wall stress compared with CLVH
and controls, with a statistically significant difference between
groups by multivariate ANOVA combining both parameters as
dependent variables (Fig. 10A). In contrast, these ratios were
similar to control values in CLVH and shunt animals, indicating that the increase in ESV in shunt animals is most likely
adaptive, translates into a higher wall stress that is required to
achieve a higher SV based on the Starling principle, and does
not represent systolic failure.
1276
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
residual Ees accounts for Ea and passive stiffness (two statistically independent physical determinants of Ees) through
multiple linear regression. We thoroughly demonstrate the
limitations of these approaches in commonly used rat models
of POH and VOH. Baan and Van der Velde (3) have shown
that Ees increased in response to acutely increased afterload,
while Sodums et al. (43) observed a leftward shift of the
ESPVR intercept (decreased Vo) in response to acutely increased afterload.
In our POH (chronically increased afterload) animals with
CLVH, Vo was not significantly decreased (Table 4, top and
middle), while Ees was significantly increased in mild longterm POH, but not with CLVH, after 4 mo of more severe POH
(Fig. 6, A and B); however, in partial agreement with both
reports (3; 43), and with Little et al. (31), CLVH animals had
higher than normal values of indicators combining Ees and Vo
(Table 4, top and middle). Thus, taking together our study and
previous reports, chronic and acute increases in afterload may
indeed lead to a left shift of ESPVR, whether it is by increased
Ees, reduced Vo, or both (3, 31, 43).
In POH complicated by overt systolic failure (DCM), Vo was
shifted to the right (Table 4, top), but Ees was significantly higher
than that in sham animals (Fig. 6A), leading to combined indicators that varied widely (Table 4, top). As shown in Table 4, top,
ESP measured at an ESV of 800 ␮l by conductance was significantly lower in DCM than CLVH, thus correctly measuring
decompensation within POH, and its point estimate was lower
than that of control counterparts, although this difference failed to
reach statistical significance (Table 4, top). The integrated ESPVR
from Vo to 800 ␮l by conductance was significantly lower in
DCM than in CLVH and controls (Table 4, top), adequately
reflecting systolic failure in that setting.
Regarding PRSW, the acute study by Little et al. (31) found
this parameter to be afterload independent, and the acute study
by Van den Bergh et al. (50) concluded that PRSW was the
preferred indicator in mice based on its sensitivity to inotropy
and its load independence. Moreover, in the chronic study by
Borlaug et al. (8) on hypertensive patients with heart failure
and preserved LVEF, Ees was increased, but PRSW was
significantly lower than that of controls. In contrast with these
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Fig. 6. Box plots of baseline end-systolic elastance (Ees), arterial elastance (Ea), and Ees-to-Ea ratio (Ees/Ea) in animal models of pressure and volume overload.
At baseline, Ees and Ea were variably increased in POH and decreased in VOH. Ees/Ea is preserved in POH and reduced in chronic VOH. A: POH. Ees: P ⫽
0.016 by ANOVA, P ⫽ 0.048 for DCM vs. sham 4 mo. Ea: P ⫽ 0.003 by ANOVA, P ⫽ 0.02 for DCM vs. sham 4 mo, P ⫽ 0.042 for DCM vs. normal,
P ⫽ 0.03 for CLVH vs. sham 4 mo. Ees/Ea: P ⫽ 0.13 by ANOVA. B: mild POH. Ees: P ⫽ 0.006, Ea: P ⫽ 0.026, Ees/Ea: P ⫽ 0.21. C: VOH 3 mo. Ees:
P ⬍ 0.0001, Ea: P ⬍ 0.0001, Ees/Ea: P ⫽ 0.025.
Ventricular Stiffness and Performance in Chronic Loading
•
1277
Chemaly ER et al.
Table 4. Other load-adjusted indicators of left ventricular systolic function in animal models used in the study
Group
Parameter
PRSW, mmHg
Vo of ESPVR, ␮l
ESP at 800 ␮l, mmHg
Integrated ESPVR from Vo to
800 ␮l, mmHg ⫻ ␮l
Pressure overload hypertrophy (aortic banding 4 mo)
CLVH
Mean
SD
n
P vs. sham
P vs. normal
DCM
Mean
SD
n
P vs. sham
P vs. CLVH
P vs. normal
Normal
194
92
17
0.41 (0.0055
uncorrected)
0.02
0.34 (0.0022
uncorrected)
78
31
8
62
28
5
0.0005
570
429
17
0.001
353
88
5
0.045
0.08 (0.001
uncorrected)
93
141
17
1.00
⬍0.001
⬍0.001
⬍0.001
0.30
⫺119
178
8
⫺196
303
5
⬍0.0001
189
52
8
156
24
5
0.0006
190765
66400
5
⬍0.001
⬍0.001
35626
31992
17
0.16 (0.01 uncorrected)
⬍0.001
0.02
85391
23282
8
78733
30502
5
⬍0.0001
Mild pressure overload hypertrophy (aortic banding 6 mo)
CLVH
Sham-6 mo
Mean
SD
n
P vs. sham
Mean
SD
n
161
63
4
0.047
71
34
4
⫺172
25
4
0.71
⫺217
225
4
347
95
4
0.01
143
70
4
168439
46010
4
0.049
77763
57281
4
92
73
14
0.005
221
91
5
71205
54691
14
0.38
96448
49124
5
Volume overload hypertrophy 3 mo
Shunt-3 mo
Sham-3 mo
Mean
SD
n
P vs. sham
Mean
SD
n
62
27
13
0.25
78
20
5
⫺299
845
14
0.49
⫺23
221
5
n, No. of animals. ESP, end-systolic pressure; ESPVR, end-systolic pressure volume relationship; Vo, volume intercept of ESPVR; PRSW, preload recruitable
stroke work.
reports, we show, in our chronic POH study, PRSW to be
supranormal in CLVH and failing to decrease in rats with
DCM, with even a higher point estimate compared with control
counterparts (Table 4, top).
Thus an important potential drawback of the classical loadadjusted indicators of LV systolic performance evaluated in
Table 4 is their consistently supranormal values in the compensated POH animals (Table 4, top and middle), known to
Fig. 7. Box plots of baseline end-diastolic P-V relationships (EDPVR) slope in animal models of pressure and volume overload. At baseline, the slope of EDVR
was increased in POH. A: POH. P ⬍ 0.0001 for ANOVA, P ⬍ 0.001 for CLVH vs. sham and normal, P ⫽ 0.004 for DCM vs. sham, and P ⫽ 0.001 for DCM
vs. normal. B: mild POH. P ⫽ 0.08. C: VOH 3 mo. P ⫽ 0.27.
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Sham-4 mo
Mean
SD
n
Mean
SD
n
P for ANOVA
⫺288
261
5
1.00
1.00
420
330
5
0.002
0.001
1278
Ventricular Stiffness and Performance in Chronic Loading
•
Chemaly ER et al.
have normal or reduced cellular function (16), with normal or
reduced ex vivo function (42). They appear, however, to fall
adequately in DCM facing POH, although they do so with
notable variability (Table 4, top).
This further indicates their stiffness dependence and afterload dependence, as opposed to SV/wall stress ratios, which
remain normal in CLVH and reduced in DCM, in agreement
with cellular function in the setting of POH, with or without
heart failure (16).
The indicators studied in Table 4 were either normal or
reduced in VOH (Table 4, bottom), and this is further discussed.
We consider LVEF to be the simplest of the preloadadjusted indicators of LV systolic performance (26).
LVEF correctly reflected systolic dysfunction in POH with
DCM. However, in mild POH animals with CLVH followed
for 6 mo, LVEF was significantly higher than in sham counterparts, likely from LV geometry changes. As mentioned
above, in previous studies, these animals have normal or
reduced cellular function (16), with normal or reduced ex vivo
function (42). The lower end-systolic wall stress in these
animals (Table 9, middle) adds to the complex hemodynamics
of this phenotype. By its milder pressure overload (Table 3,
middle), this group of animals resembles low gradient human
aortic valve stenosis; low flow could not be ascertained, since
SV was not significantly lower than sham (Table 2, middle).
Adda et al. (1) studied patients with severe aortic stenosis and
either low flow (low SV), low gradient, or both and demonstrated a normal LVEF, with significantly smaller LV size for
some patients, despite impaired systolic function by ventricular
strain imaging, suggesting that LVEF overestimated systolic
performance. By contrast, SV/wall stress was normal in these
animals (Fig. 10B).
In addition, we believe this is the first study to question the
validity of low LVEF as an indication of systolic dysfunction
in our low-afterload model of VOH. It is recognized that LVEF
is afterload dependent (6, 26), and LVEF is known to increase
with Ees and decrease with Ea (27). LVEF is expected to
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Fig. 8. Box plots of Ees, Ea, and Ees/Ea on dobutamine in animal models of pressure and volume overload. Ees responded variably to dobutamine, while a
consistent decrease in Ea was measured, leading to an increase in Ees/Ea in responsive animals. The response of Ees/Ea to dobutamine was blunted or reduced
in almost all disease models. A: POH. Ees: P ⬍ 0.0001 for G, P ⫽ 0.055 for GD interactions (uncorrected). Ea: P ⬍ 0.0001 for G, P ⬍ 0.0001 for D (Huynh-Feldt
correction), P ⬍ 0.0001 for GD interactions (Huynh-Feldt correction). Ees/Ea: P ⬍ 0.0001 for G, P ⫽ 0.01 for D (Huynh-Feldt correction), P ⫽ 0.0017 for GD
interactions (Huynh-Feldt correction). B: mild POH. Ees: P ⫽ 0.032 for D (uncorrected). Ea: P ⫽ 0.041 for D (Huynh-Feldt correction). Ees/Ea: P ⫽ 0.044 for
D (Huynh-Feldt correction). C: VOH 3 mo. Ees: P ⬍ 0.0001 for G, P ⫽ 0.0498 for D (Huynh-Feldt correction), P ⫽ 0.046 for GD interactions (Huynh-Feldt
correction). Ea: P ⬍ 0.0001 for G, P ⬍ 0.0001 for D (Huynh-Feldt correction), P ⫽ 0.029 for GD interactions (Huynh-Feldt correction). Ees/Ea: P ⬍ 0.0001
for G, P ⫽ 0.0003 for D (Huynh-Feldt correction), P ⫽ 0.005 for GD interactions (Huynh-Feldt correction). P values are for repeated-measurements ANOVA.
Ventricular Stiffness and Performance in Chronic Loading
•
1279
Chemaly ER et al.
Table 6. Residual Ees associated with volume overload by
aorta-cava shunt at 3 mo after adjusting for Ea and EDPVR
Parameter
EDPVR
Ea
Shunt (shunt ⫽ 1 if aorta cava shunt
at 3 mo, shunt ⫽ 0 if control)
Intercept
Regression Coefficient
P Value
0.14 ⫾ 1.2
0.39 ⫾ 0.12
0.91
0.003
⫺0.06 ⫾ 0.03
0.09 ⫾ 0.04
0.02
0.036
Values are means ⫾ SE; N ⫽ 41 observations. Dependent variable is Ees.
Model R2 ⫽ 0.57.
increase or remain normal in chronic volume overload until
more advanced pathological stages: in clinical mitral regurgitation, LVEF remains within the normal range, despite significant muscle dysfunction (6). In aortic regurgitation, postoperative recovery is impaired once LVEF falls below normal (6).
Thus the well-demonstrated early and significant reductions in
Table 5. Residual Ees associated with DCM after adjusting
for Ea and EDPVR
Parameter
Regression Coefficient
P Value
EDPVR
Ea
DCM (DCM ⫽ 1 if DCM, DCM ⫽ 0
if control)
Intercept
1.61 ⫾ 1.70
0.54 ⫾ 0.28
0.35
0.06
0.11 ⫾ 0.07
0.02 ⫾ 0.08
0.15
0.81
Values are means ⫾ SE; N ⫽ 44 observations. Dependent variable is
end-systolic elastance (Ees). Model R2 ⫽ 0.41. Ea, arterial elastance; EDPVR,
slope of the LV end-diastolic pressure-volume relationship.
Table 7. Differential dose response of Ees adjusted on Ea
and EDPVR to dobutamine in DCM (pressure-overload
induced heart failure) and control animals
Parameter
Regression Coefficient
P Value
EDPVR
Ea
DCM (DCM ⫽ 1 if DCM, DCM ⫽ 0
if control)
Dobutamine dose
DCM-dobutamine interaction
Intercept
0.91 ⫾ 0.56
0.53 ⫾ 0.13
0.11
⬍0.001
0.13 ⫾ 0.042
0.029 ⫾ 0.0082
⫺0.035 ⫾ 0.010
0.034 ⫾ 0.042
0.003
0.001
0.001
0.41
Values are means ⫾ SE; N ⫽ 150 observations. Dependent variable is Ees.
Model R2 ⫽ 0.34.
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Fig. 9. Scatter plot of Ees vs. Ea and EDPVR slope at baseline in animal
models of pressure and volume overload. Ees was significantly correlated to Ea
(A) and to the slope of EDPVR (B) at baseline.
LVEF in the low afterload aorta-cava shunt model, with
demonstrated reversibility of cardiac remodeling (24) and preserved cellular shortening (41), are surprising in light of what
is known about LVEF in volume-overload valvular diseases.
Importantly, these animals did not develop heart failure in our
study and maintained dobutamine response by most indicators
(Figs. 3 and 4), except Ees/Ea (Fig. 8) and residual Ees (Table
8). Moreover, the high ESV observed by us and others in this
model is incompatible with a hyperdynamic circulation with
low afterload, and, unlike high EDV, high ESV does not purely
reflect volume overload.
Knowing that dilatation in these models is necessary to increase
the SV (6), we hypothesized that the required increase in loading
necessitated increases in wall stress throughout the cardiac cycle
and not just at end-diastole. Considering the very compliant
ventricle facing a low afterload, with lower ESP at equal ESV
(Table 4, bottom), an increase in ESV, leading to a lower LVEF,
may be needed to achieve the required wall stress. In confirmation
of our hypothesis, the SV/wall stress was preserved in shunt
animals (Fig. 10C), contradicting the low LVEF. Therefore, our
results suggest a distinct compliance dependence and a distinct
pattern of “reverse afterload dependence” of LVEF in this model
of VOH. Taken together with the normal SV/wall stress, the
findings in Table 4, bottom, of normal PRSW and integrated
ESPVR support normal systolic function in VOH, and the reduced
ESP at equal ESV (to the same point estimate as DCM) more
likely represents the low afterload and high compliance of this
VOH model (Table 4, bottom).
The primary hemodynamic findings in the models used in
our study are consistent with previous reports of rat models of
POH (36) and VOH (24), although other studies have shown
reduced PRSW in chronic aorta-cava shunt in rats (24).
Our dobutamine response in normal and sham rats with
respect to Ees and Ea is similar to previous data on piglets (11).
Moreover, Blaudszun and Morel (5) recently studied the ef-
1280
Ventricular Stiffness and Performance in Chronic Loading
Table 8. Differential dose-response of Ees adjusted on Ea
and EDPVR to dobutamine in aorta-cava shunt animals
(volume-overload hypertrophy, 3 mo) and control animals
Parameter
Regression Coefficient
EDPVR
Ea
shunt (shunt ⫽ 1 if shunt, shunt ⫽ 0
if control)
Dobutamine dose
Shunt-dobutamine interaction
Intercept
⫺0.36 ⫾ 1.15
0.40 ⫾ 0.12
⫺0.070 ⫾ 0.028
0.025 ⫾ 0.0056
⫺0.020 ⫾ 0.0070
0.088 ⫾ 0.035
P Value
0.76
0.001
0.014
⬍0.001
0.005
0.015
Values are means ⫾ SE; N ⫽ 120 observations. Dependent variable is Ees.
Model R2 ⫽ 0.46.
Chemaly ER et al.
ESPVR in rats after a single injection of 1 mg/kg of
dobutamine (46). In contrast with our study, ESPVR was
obtained by increasing the afterload through a gradual
occlusion of the ascending aorta (46). They observed a
shifting to the left of the linear ESPVR, with an increased
slope (46). This latter study stresses the importance of the
afterload in assessing the effects of dobutamine (46). More
recently, Connelly et al. (15) studied the ESPVR of rats by
IVC occlusion immediately after a single 4 ␮g/kg intravenous bolus of dobutamine. They found an increase in the
slope of the ESPVR; however, the ESP at steady state was
increased by 25 mmHg, suggesting a hypertensive response
to the bolus (15). Using dobutamine infusions, like in our
study and the study by Blaudszun and Morel (5), instead of
boluses may also explain differences between studies through a
different vasodilator-inotrope balance.
In other species, the study by Crottogini et al. (17) on
dogs reports a left shift of ESPVR on dobutamine, together
with an increase in peak LV pressure; similarly, Gayat et al.
(21) recently reported the dobutamine response of ESPVR
recorded noninvasively in healthy human volunteers and
found an increase in Ees, a stable Ea, and an increase in
systolic pressure.
Importantly, we show the dobutamine response of all indicators to be reduced in DCM and compensated severe POH and
preserved in mild POH and in VOH.
Fig. 10. Box plots of SV-to-wall stress ratios (SV/wall stress) in animal models of pressure and volume overload. In contrast with the load-adjusted indicators,
the SV/wall stress was normal in all compensated models of POH and VOH and markedly reduced in DCM (see text). A: POH. SV/end-diastolic wall stress:
P ⬍ 0.0001 for ANOVA, DCM lower than all (P ⬍ 0.001). SV/end-systolic wall stress: P ⫽ 0.030 for ANOVA, DCM lower than CLVH (P ⫽ 0.02); P ⬍ 0.001
for DCM vs. normal and sham if Bonferroni correction does not include CLVH. P ⬍ 0.0001 for Wilks’ lambda by multivariate ANOVA (MANOVA). B: mild
POH. SV/end-diastolic wall stress: P ⫽ 0.79. SV/end-systolic wall stress: P ⫽ 0.19. P ⫽ 0.37 for Wilks’ lambda by MANOVA. C: VOH 3 mo. SV/end-diastolic
wall stress: P ⫽ 0.24. SV/end-systolic wall stress: P ⫽ 0.92. P ⫽ 0.50 for Wilks’ lambda by MANOVA.
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fects of dobutamine infusion at progressive rates in rats and
found no increase in Ees. The dobutamine effect we observe is
dominated by a reduction in Ea, with a relatively stable Ees,
resulting in an increase in Ees/Ea (Fig. 8). This most likely
reflects opposing effects of increased inotropy and decreased
afterload on Ees in our study and serves as additional evidence
of the partial afterload dependence of Ees. We were surprised
by the significant vasodilator effect of dobutamine in our
hands, ascertained by the response of LV maximal pressure to
dobutamine as either decreased or unchanged in normal animals, despite an evident inotropic effect (increased dP/dtmax;
Figs. 2 and 3). Tachibana et al. studied the shift of the
•
Ventricular Stiffness and Performance in Chronic Loading
Table 9. End-diastolic and end-systolic wall stress
Group
Parameter
End-diastolic Wall
Stress, mmHg
Pressure overload hypertrophy
Mean
SD
n
P vs. sham
P vs. normal
CLVH
DCM
Normal
Sham-4 mo
(aortic banding 4 mo)
4.78
6.78
1.63
4.21
7
7
1.00
1.00
1.00
1.00 (0.029
uncorrected)
16.82
42.56
5.55
17.42
17
17
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
⬍0.001
4.90
11.91
1.22
3.92
8
8
5.59
10.81
0.80
3.32
5
5
⬍0.0001
⬍0.0001
Mild pressure overload hypertrophy (aortic banding 6 mo)
CLVH
Sham-6 mo
Mean
SD
n
P vs. sham
Mean
SD
n
3.15
1.33
4
0.33
4.00
0.88
4
4.98
3.42
4
0.043
10.01
1.95
4
Volume-overload hypertrophy 3 mo
Shunt-3 mo
Sham-3 mo
Mean
SD
n
P vs. sham
Mean
SD
n
9.48
5.14
14
0.046
4.38
1.53
5
22.68
8.99
14
0.014
11.38
1.41
5
n, No. of animals.
Limitations and Future Directions
Our study has specific conceptual and practical limitations.
We studied multiple models of cardiac hypertrophy and failure
and aimed for experimental conditions to be as consistent as
possible. As mentioned earlier, we were able to achieve comparable levels of LV hypertrophy between POH and VOH,
along with comparable levels of LV maximal pressure between
POH-CLVH and POH-DCM. Nonetheless, we still found significantly lower heart rates in DCM and shunt 3-mo animals
than in other groups in Tables 2 and 3. These findings are most
likely related to different cardiac effects of sedation between
groups. The nonfailing rats, whether CLVH or sham/normal
rats, have, in our experience, a narrow therapeutic index with
either ketamine or isoflurane; thus increasing anesthetic dose to
reduce the heart rate of these animals by an 11% relative value
would have been challenging. In Table 3, the heart rate was
significantly lower in shunt 3-mo compared with sham 3-mo
animals during invasive hemodynamic recording (P ⫽ 0.042).
However, the heart rate of the shunt 3-mo group was comparable to the heart rate of the other control groups in Table 3,
while the heart rate of the sham 3-mo group was higher,
indicating, in this latter case, a lower sensitivity of this partic-
Chemaly ER et al.
1281
ular group of healthy rats to the anesthetic. The potential
consequences of these differences in heart rate are threefold.
First, the reduced heart rate under sedation/anesthesia may be
a surrogate for hemodynamic depression by the sedative, as
shown in mice (51). However, this 11% reduced heart rate is
unlikely to account for the doubling of EDV and the severalfold increase in ESV, as well as the profoundly reduced
ejection fraction in the DCM group by echocardiography
(Table 2). Second, heart rate can affect contractility through the
force-frequency relationship (Bowditch effect). In normal ventricular myocardium, including rat myocardium, the forcefrequency relationship is positive (9, 19), although a negative
or triphasic force-frequency relationship was observed in normal rat myocardium (34). One study evaluated the positive
force-frequency relationship of rat myocardium within the physiological heart rate of 6 – 8 Hz (30). In that study, relative changes
of ⬍20% in the tension of rat RV trabeculae were measured with
1-Hz change in stimulation frequency (30). However, since the
force-frequency relationship is reversed in failing myocardium,
including in rats (9), the rather slight increases in heart rates
observed in our study in nonfailing animals (CLVH, controls)
and decreases in failing animals (DCM) may have all caused an
increase in inotropy. Third, heart rate can affect ventricular
filling; however, it is unlikely that the doubled LV volumes in
DCM animals are due to the 11% decrease in heart rate
compared with CLVH (Table 2, top). Similarly, it is unlikely
that the major increase in LVEDP of DCM animals is due to
this relative bradycardia (Table 3, top). As we noted, this
increase in LVEDP is corroborated by RV hypertrophy in
DCM animals (Table 2, top).
Another limitation is our use of a linear fit for the ESPVR
and the EDPVR characteristics, known to be curvilinear in
rodents when constructed in the full range of variation of LV
volume (48). However, the in vivo ESPVR and EDPVR are
obtained during IVC occlusion over a limited interval within
which a linear fit is possible. Based on this consideration, Ees
in that range is meaningful, but the intercept Vo is a “virtual”
intercept, the mathematical Vo of the in vivo constructed
ESPVR characteristic, and not Vo in the sense of the real value
of ESV when ESP ⫽ 0, as stated earlier by Tachibana et al.
(46). Negative Vo of linear and curvilinear ESPVR obtained in
vivo are reported in other species (2). In that case, Vo retains its
value as an indicator of the left or right shift of the ESPVR,
which is an important characteristic (10).
In a direct physiological measure of Vo used by us and
others (42, 49), the LV volume is controlled by a balloon
inserted in the LV of a nonworking isolated heart with retrograde perfusion; thus unloading the ventricle to a systolic
pressure of zero is feasible (unlike IVC occlusion) and does not
compromise its coronary perfusion.
Tachibana et al. (46) have applied an approach in which they
recorded in vivo P-V loops with a conductance catheter and
incorporated in the ESPVR a Vo measured postmortem after
rigor contracture. However, a major limitation of this procedure is the inclusion of volumes measured by two different
methods in the same curve.
Once the issue of Vo is considered, choosing a linear as
opposed to a curvilinear fit is related to the measured values
and their distribution. Indeed, our experiments on ex vivo rat
use an exponential fit for ESPVR (42, 48, 49). In that case, the
parameters of the exponential curve are dependent on the shape
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Mean
SD
n
P vs. sham
P vs. CLVH
P vs. normal
Mean
SD
n
Mean
SD
n
P for ANOVA
End-systolic Wall
Stress, mmHg
•
1282
Ventricular Stiffness and Performance in Chronic Loading
Chemaly ER et al.
Our ability to generalize our results may be limited by the
use of “extreme” models: severe POH with massive hypertrophy and ensuing dilatation, and VOH by aorta-caval shunt.
Thus our results on POH only partially agree with the conceptually similar, clinical study by Borlaug et al. (8) on Ees. Also,
because of differences in afterload and wall stress, conclusions
on VOH by aorta-cava shunt need to be applied with caution to
the more clinically relevant aortic and mitral regurgitations.
However, in these valvular conditions, we can expect SV/wall
stress to be a more sensitive and specific breakpoint in the
natural history of the disease, and its response to load-modifying medical therapy, than LVEF. In VOH models, initial
dilatation reflects volume overload, and decreases in LVEF
would await dilatation secondary to ventricular decompensation; in contrast, SV/wall stress incorporates two indexes of
decompensation, dilatation and rising filling pressures, and is
expected to drop with increases in any of the two.
We did calculate a residual Ees, thus measuring a component of ventricular stiffness not attributed to the more passive
EDPVR and not transmitted from the afterload Ea. We do
show this residual Ees to reflect the acute inotropic effect of
dobutamine; however, it is not clear why the adjusted residual
Ees does not decrease and may still increases in POH with
DCM and decreases in VOH. We are aware of one study
measuring cellular stiffness in POH and attributing cellular
stiffening to microtubule accumulation; the latter leading to
impaired cell shortening (47). Interestingly, this microtubule
accumulation does not occur in VOH (16).
Conclusion
We believe our study to be the first to address the limited
value, mainly due to stiffness dependence and afterload dependence, of most load-adjusted parameters of LV systolic performance in chronic POH and VOH alike. We used highstiffness and high-compliance models of POH and VOH and
compared them side by side and facing dobutamine challenge.
We also show LVEF to be stiffness dependent in VOH.
We propose the SV/wall stress as a load-adjusted and stiffness-adjusted indicator of systolic performance. Gaash et al.
(20) and others (16) have expressed LV shortening-wall stress
relationships. Indeed, changes in LV loading variably combine
changes in pressure and changes in dimension. Pressure and
dimension “interconvert” through compliance; thus a load
measurement using one of the two is compliance dependent.
Wall stress, in contrast, is a pressure-dimension product that
overcomes this compliance dependence. We show the superiority of this indicator in VOH. In clinical studies of POH and
CLVH, low SV and normal LVEF are demonstrated, due to
small ventricles (1) and likely normal wall stress; in that
setting, SV/wall stress may conversely be more sensitive than
LVEF in measuring systolic dysfunction in some forms of
POH as well. Measuring SV/wall stress has also attractive
therapeutic implications: understanding and preventing the
potential loss of forward flow in stiff ventricles subjected to
small reductions in filling volumes for the treatment of congestive heart failure, resulting (through stiffness) in larger
reductions in filling pressures, leading to underloading by loss
of wall stress, and leading to loss of SV.
Our proposed indicator also has important physiological
significance: SV was preserved between animal groups of
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of the curve and may not reflect LV systolic function (42). This
drawback has led to the use of alternative indicators similar to
those used with linear in vivo ESPVR, which are the ESP at a
given ESV, or an integration of the ESPVR (42); moreover, the
exponential ESVR has been linearized and converted to an
equivalent maximal elastance, which is equivalent to Ees (48).
Obtaining the ESPVR over a limited volume interval compatible with in vivo measurements makes the integration of the
full ESPVR (Figs. 1 and 5) used in Table 4 problematic. We
aimed at generalizing the approach of Crottogini et al. (17),
who used the area under a linear ESPVR to measure withinanimal changes of systolic performance, within the operating
pressure and volume interval of that particular animal, as also
done more recently by Blaudszun and Morel (5). The integration approach has the advantage of generating, over a range of
ESP and ESV, one numeric value that increases if Ees increases or Vo decreases and appears to correctly delineate
systolic failure in DCM animals and shows normal values in
VOH animals, with supranormal values in CLVH animals as a
drawback (Table 4).
Another limitation is the measurement of SV/wall stress. We
suggest using the end-diastolic and end-systolic wall stress,
but, ideally, more comprehensive parameters integrating the
ejected volume to the wall stress throughout the cardiac cycle
are needed. In our study, we obtained LV dimensions by echocardiography and subsequent pressure measurements through LV
apical stab on open-chest animals. Simultaneous imaging-pressure collection, or sonomicrometry, allowing continuous measurement of LV chamber size and wall thickness, would permit
SV/wall stress measurement in occlusion studies and with
dobutamine challenge. Pressure sensors can be inserted percutaneously (or more generally through a closed-chest approach),
allowing echocardiography to be performed simultaneously
with pressure measurements.
A SV-wall stress characteristic curve obtained by inferior
vena-caval occlusion is expected to provide a range of variation of SV within a range of wall stress, which is more
representative than a steady-state single-point estimate. Integrating the curve summarizes that information. The slope (or
derivative) of this curve may inform on the load dependence of
performance at a cellular level, and future studies are needed to
correlate this indicator to cellular stiffness (47).
SV and wall stress are potentially obtainable with noninvasive measures. Nevertheless, this is challenging with the currently available technology. LV volumes and wall thickness
are classically obtained by imaging. Noninvasive LVESP can,
in fact, be measured as the pressure at the dicrotic notch
(incisura) of the aortic pressure tracing obtained by carotid
aplanation tonometry, as reported recently by Gayat et al. (21).
However, the aortic pressure at the incisura may not be an
accurate reflection of the LVESP in patients with diseased
aortic valves (aortic stenosis and regurgitation); and these
patients are precisely the ones in most need of improved
systolic function parameters. Regarding noninvasive LVEDP
measurement, multiple echocardiographic indicators of LV
diastolic function are known to predict LVEDP in a semiquantitative manner, as most recently studied by Rafique et al. (40).
To our knowledge, these popular echocardiographic measures
do not give a point estimate of the end-diastolic pressure of an
individual patient (35).
•
Ventricular Stiffness and Performance in Chronic Loading
POH, indicating its vital and homeostatic role; SV was appropriately increased in the VOH due to shunt flow. Reduction in
SV as a result of heart failure would indicate advanced stages.
Wall stress is also physiologically relevant as an indicator of
loading sensed at the cellular level (18).
Finally, although our study demonstrates the usefulness of
this index in chronic loading, we are confident that it will also
perform well in other surgical models of cardiac dysfunction,
under pharmacological challenge, and in transgenic models. In
the particular case of ischemic cardiomyopathy following myocardial infarction, reductions in LVEF and Ees are classical
(39). However, it is known that the viable myocardium after
infarction remodels through VOH (25); the latter process may
contribute to the changes seen in classical P-V parameters, and
measuring SV/wall stress would more specifically assess systolic decompensation.
GRANTS
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: E.R.C., S.S., and R.J.H. conception and design of
research; E.R.C. and A.H.C. performed experiments; E.R.C. analyzed data;
E.R.C. and R.J.H. interpreted results of experiments; E.R.C. prepared figures;
E.R.C. drafted manuscript; E.R.C., A.H.C., and R.J.H. edited and revised
manuscript; E.R.C., A.H.C., S.S., and R.J.H. approved final version of manuscript.
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This work was supported by Leducq Foundation through the Caerus network
and by National Heart, Lung, and Blood Institute Grants R01 HL093183,
HL088434, HL071763, HL080498, HL083156, and P20HL100396 (R. J. Hajjar)
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