Download Normal myocardial function in severe right ventricular volume

Am J Physiol Heart Circ Physiol
280: H11–H16, 2001.
Normal myocardial function in severe right
ventricular volume overload hypertrophy
YUJI ISHIBASHI,1 JUDITH C. REMBERT,2 BLASE A. CARABELLO,1 SHINTARO NEMOTO,1
MASAYOSHI HAMAWAKI,1 MICHAEL R. ZILE,1 JOSEPH C. GREENFIELD, JR.,2
AND GEORGE COOPER IV1
1
Gazes Cardiac Research Institute, Medical University of South Carolina, and Department of
Veterans Affairs Medical Center, Charleston, South Carolina 29403; and 2Cardiology Division,
Department of Medicine, Duke University Medical Center and Department of Veterans Affairs
Medical Center, Durham, North Carolina 27705
Ishibashi, Yuji, Judith C. Rembert, Blase A. Carabello, Shintaro Nemoto, Masayoshi Hamawaki, Michael R. Zile, Joseph C. Greenfield, Jr., and George
Cooper, IV. Normal myocardial function in severe right
ventricular volume overload hypertrophy. Am J Physiol
Heart Circ Physiol 280: H11–H16, 2001.—Severe left ventricular volume overloading causes myocardial and cellular
contractile dysfunction. Whether this is also true for severe
right ventricular volume overloading was unknown. We
therefore created severe tricuspid regurgitation percutaneously in seven dogs and then observed them for 3.5–4.0 yr.
All five surviving operated dogs had severe tricuspid regurgitation and right heart failure, including massive ascites,
but they did not have left heart failure. Right ventricular
cardiocytes were isolated from these and from normal dogs,
and sarcomere mechanics were assessed via laser diffraction.
Right ventricular cardiocytes from the tricuspid regurgitation dogs were 20% longer than control cells, but neither the
extent (0.171 ⫾ 0.005 ␮m) nor the velocity (2.92 ⫾ 0.12 ␮m/s)
of sarcomere shortening differed from controls (0.179 ⫾ 0.005
␮m and 3.09 ⫾ 0.11 ␮m/s, respectively). Thus, despite massive tricuspid regurgitation causing overt right heart failure,
intrinsic right ventricular contractile function was normal.
This finding for the severely volume-overloaded right ventricle stands in distinct contrast to our finding for the left
ventricle severely volume overloaded by mitral regurgitation,
wherein intrinsic contractile function is depressed.
mitral regurgitation; cardiocyte contractile function
PATHOLOGICAL VENTRICULAR VOLUME OVERLOADING is caused
by a variety of structural and metabolic abnormalities.
Experimental models of pathological left ventricular
(LV) volume overloading have shown that, as in humans, if not initially lethal it may be tolerated for an
extended period of time, but left heart failure develops
eventually if a sustained volume overload is severe. In
mitral regurgitation, this is based on muscle dysfunction at the level of the ventricle and of its constituent
cardiocytes (29), which in turn appears to be caused by
Address for reprint requests and other correspondence: G. Cooper,
IV, Gazes Cardiac Research Institute, P.O. Box 250773, Medical
Univ. of South Carolina, 114 Doughty St., Charleston, SC 29403
(E-mail: [email protected]).
http://www.ajpheart.org
myofibrillar lysis (29), abnormalities of the force-frequency relationship, and calcium metabolism (2, 18).
Right ventricular (RV) volume overloading appears
to be better tolerated than LV volume overloading. We
have found, for instance, that experimental animals
with severe RV volume overloading caused by atrial
septal resection, which results in a ratio of pulmonary
to systemic blood flow as great as 4:1, exhibit normal
RV muscle function and energetics for at least 6 mo (8).
Furthermore, humans with similarly severe RV volume overloading caused by atrial septal defects exhibit
normal RV systolic function indefinitely if pulmonary
hypertension with consequent RV pressure overloading does not supervene (16). However, because the
geometry of the RV makes separation of loading conditions from intrinsic contractility difficult and because
the calculations of wall stress often used to estimate
RV loading are extremely complex and remain largely
unvalidated, intrinsic RV contractility has been difficult to assess (20, 23).
Over the past decade, we have shown that, for both
normal and abnormal myocardium, the contractile
function of isolated cardiocytes assessed in vitro mirrors the intrinsic contractile function in vivo of the
ventricle from which the cardiocytes were isolated (15,
29). We therefore used this principle here to test the
hypothesis that intrinsic contractile function is normal
in long-term, severe RV volume overloading.
METHODS
Animal models. Mongrel dogs of random sex weighing
25–35 kg were the subjects of this study. For the creation of
tricuspid regurgitation, anesthesia in dogs sedated with morphine was induced with thiopental sodium (15 ml iv). After
intubation, we maintained anesthesia by inhalation of halothane (5% initially, followed by 0.2–0.5%). All procedures
and the care of the dogs were in accordance with institutional
guidelines, which meet or exceed those of the American
Physiological Society and the American Association for AcThe 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.
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Received 9 February 2000; accepted in final form 1 August 2000
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MYOCARDIAL FUNCTION IN TRICUSPID REGURGITATION
Table 1. Hemodynamic profiles
Table 2. Dimensions of RV cardiocytes
Characteristics
Control
TR
Ascites, peripheral edema
Right atrial pressure (a wave), mmHg
Right atrial pressure (v wave), mmHg
RV systolic pressure, mmHg
RV end-diastolic pressure, mmHg
Aortic systolic pressure, mmHg
⫺
4.5 ⫾ 0.3
3.6 ⫾ 0.4
26.7 ⫾ 1.8
4.1 ⫾ 0.7
117.7 ⫾ 5.3
⫹
4.1 ⫾ 0.8
17.8 ⫾ 2.5*
24.7 ⫾ 1.7
15.4 ⫾ 0.5*
113.3 ⫾ 4.2
Values are mean ⫾ SE; n ⫽ 7 control dogs and 5 tricuspid
regurgitation (TR) dogs. a, peak a wave pressure; v, peak v wave
pressure; RV, right ventricular. * P ⬍ 0.001 for a difference from
control value by Student’s unpaired t-test.
Fig. 1. Right ventriculography of a dog
with tricuspid regurgitation. The contrast material was injected at a rate of
15 ml/s, and the images were taken in
the left anterior oblique position. Left:
heart at end diastole; right: heart at end
systole. The short arrows indicate the
right atrium, and the long arrows indicate the right ventricle (RV). Note the
denser opacification of the right atrium
than of the RV in left and incomplete
ejection of contrast material from the
right atrium in right.
TR
156 ⫾ 3
34 ⫾ 1
187 ⫾ 4*
40 ⫾ 1*
Values are mean ⫾ SE; n ⫽ 44 control dogs and 63 TR dogs. * P ⬍
0.001 for a difference from control value by Student’s unpaired t-test.
used before in evaluating our model of surgically created
mitral regurgitation (3, 29).
Cardiocyte isolation. Immediately after the in vivo evaluation of cardiac function by one subset of investigators, and
after the dogs were more deeply anesthetized, another subset
of investigators, who were not informed of the results of this
evaluation, isolated and evaluated cardiocytes from these
same RVs as follows. A right lateral thoracotomy was performed, the pericardium was excised, and the right coronary
artery was isolated. The heart was removed and placed in
cold, nominally calcium-free buffer of the following composition (in mM): 13.0 NaCl, 4.8 KCl, 1.2 MgSO4, 1.2 NaH2PO4,
2.5 NaHCO3, 12.0 HEPES buffer, and 12.5 glucose; 6 mg/l
insulin was also added. The right coronary artery was cannulated immediately, and perfusion with the same buffer
was initiated. The RV free wall was removed from the rest of
the heart, and the specimen was cleared of blood by brief
perfusion with the same buffer warmed to 37°C and gassed
with 100% O2. The method then used to dissociate cardiocytes from the canine RV was modified from that previously
reported by us for the canine LV (29): perfusion was continued for 25 min at 37°C by recirculating the buffer, now
supplemented with 155 U/ml type II collagenase and 10 ␮M
Ca2⫹; mean pressure (⬃90 mmHg) and pH (⬃7.40) were kept
within the physiological range. Any undissociated tissue was
discarded and that remaining was placed in a chamber containing the above buffer supplemented with 0.3 mM Ca2⫹,
2.5% bovine serum albumin, and 62 U/ml of the same collagenase used for perfusion. After mincing the tissue into small
pieces with scissors, we gently agitated the tissue for 5 min at
37°C in the same buffer while gassing the tissue with 100%
oxygen. Dissociated cardiocytes were harvested by passing
the supernatant through a 210-␮m nylon mesh and collecting
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creditation of Laboratory Animal Care. Tricuspid regurgitation was created in seven dogs by a modification (1, 10) of the
closed-chest, catheter-based method that we use for creating
mitral regurgitation (3, 29). Of note, in contrast to the transient hemodynamic instability often seen after surgically
created mitral regurgitation (29), this did not occur after
surgically created tricuspid regurgitation. Seven normal dogs
served as controls. After recovery, we maintained each operated dog on a standard canine diet for 3.5–4.0 yr. Two
operated dogs experienced unobserved sudden death at the
end of the study period. At final study, each remaining dog
was lightly anesthetized with intravenous fentanyl-droperidol and inhaled nitrous oxide-oxygen, a combination having
little effect on myocardial contractile function (29). To prevent the confounding influences of changing adrenergic tone
on inotropic state and heart rate during estimations of contractility, measurements of ventricular function were made
in a ␤-blocked state, as validated by isoproterenol challenge
(29), induced by a loading dose of esmolol (0.5 mg 䡠 kg⫺1 䡠
min⫺1 iv for 3 min) followed by a constant infusion of esmolol
(0.3 mg 䡠 kg⫺1 䡠 min⫺1 iv). Sheaths for arterial and venous
access were placed in the femoral region, and systemic arterial pressures were monitored. After measuring right-sided
pressures with a Swan-Ganz catheter, we performed left and
right ventriculography with the use of a pigtail catheter for
the LV and a Nishiya catheter (22) for the RV. These procedures for evaluating ventricular function were based on those
Length, ␮m
Width, ␮m
Control
MYOCARDIAL FUNCTION IN TRICUSPID REGURGITATION
H13
Fig. 2. Photomicrographs of freshly isolated RV cardiocytes from a control dog
(top) and a dog with tricuspid regurgitation (bottom). The scale bar represents 25
␮m.
severe RV volume overloading causing overt right
heart failure was present in each of these dogs.
Cardiocyte morphology. Cardiocyte dimensions were
evaluated in terms of cellular length and width. As
RESULTS
Characteristics of experimental model. All of the dogs
with tricuspid regurgitation had, on physical examination, a grade III–IV/VI pansystolic murmur at the
lower left sternal border, with a readily palpable
parasternal thrill. Right heart failure, as evidenced by
marked peripheral edema and ascites, was prominent
in all dogs. As shown in Table 1, RV systolic pressure
was normal, as was aortic systolic pressure. Right
ventriculography, shown in Fig. 1, demonstrated in
each dog with tricuspid regurgitation complete and
rapid opacification of the right atrium at end systole,
and there was incomplete ejection of contrast material
from the right atrium at end diastole. Thus isolated,
Fig. 3. Display of sarcomere motion sampled at a frequency of 1 kHz
during contractions of single cardiocytes. A: RV cells from a control
dog (left) and from a dog with tricuspid regurgitation for 3.5 yr
(right). B: left ventricular (LV) cells from a control dog (left) and from
a dog with mitral regurgitation for 3 mo (right). Sarcomere mechanics were averaged for 10 contractions of each cardiocyte studied at
37°C, 2.5 mM Ca2⫹, and 0.25-Hz stimulation frequency. The data for
the LV cells, taken from our previous study (see Ref. 29), were
gathered with the same device under the same conditions.
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them by gravity. The Ca2⫹ concentration was gradually increased to 2.5 mM, after which the cells were kept for 1 h at
37°C in collagenase-free buffer before defining contractile
function.
Cardiocyte mechanics. Our methods for laser diffraction
measurement of sarcomere motion in isolated cardiocytes
have been described before (15, 29). Cells were added to 37°C,
2.5 mM Ca2⫹ buffer in a well affixed to a glass slide. Only
single, rod-shaped cells with a resting sarcomere length
ⱖ1.85 ␮m and that contracted with each stimulus and were
quiescent between stimuli were analyzed. Ten steady-state
contractions during 0.25-Hz electrical stimulation were sampled and averaged to yield a final profile of sarcomere length
and velocity versus time during contraction. Changes in
sarcomere length were measured at a sampling rate of 1 kHz
from movement of the first-order diffraction pattern cast by
light from a substage helium-neon laser passing through the
sarcomeres.
Cardiocyte morphology. Two aliquots of isolated cardiocytes from each specimen were plated in separate dishes, and
randomly selected cell images were captured on an inverted
microscope at a magnification of ⫻400 by a frame grabber.
The images were printed at a final magnification of ⫻1,100,
and cell length and width were measured manually.
Statistical analysis. The mean value and the standard
error of the mean are shown for each group of data. Differences in selected measures were evaluated via an unpaired
Student’s t-test, with a significant difference said to exist at
the level specified in each case.
H14
MYOCARDIAL FUNCTION IN TRICUSPID REGURGITATION
given numerically in Table 2 and illustrated in Fig. 2,
RV cardiocytes from the dogs with tricuspid regurgitation were significantly longer and wider than RV cardiocytes from control dogs. Both the numerical values
from and the appearance of volume-overloaded hypertrophied RV cells here are strikingly similar to those
found in our previous study (see Ref. 29; Table 4 and
Fig. 3) of volume-overloaded hypertrophied LV cells
from dogs with isolated, severe mitral regurgitation.
Cardiocyte mechanics. Representative illustrations
of sarcomere mechanics in cardiocytes from control and
tricuspid regurgitation RVs are shown in Fig. 3. Because our intent in this study was to compare intrinsic
myocardial contractile function in RV volume overloading caused by tricuspid regurgitation with that in LV
volume overloading caused by mitral regurgitation,
illustrative sarcomere mechanics from our study (29) of
cardiocytes from control and mitral regurgitation LVs
are also shown in Fig. 3. Summary data in Fig. 4 show
that the extent and velocity of sarcomere shortening in
RV cardiocytes from dogs with tricuspid regurgitation
were only slightly decreased when compared with corresponding values for cells from control dogs, with no
statistical difference; there was no significant difference between control versus tricuspid regurgitation
cardiocytes in terms of initial sarcomere length
(1.941 ⫾ 0.011 vs. 1.918 ⫾ 0.009 ␮m), time to peak
shortening (214 ⫾ 2 vs. 215 ⫾ 2 ms), peak relaxation
velocity (3.90 ⫾ 0.14 vs. 3.63 ⫾ 0.17 ␮m/s), or time to
peak relaxation velocity (39 ⫾ 2 vs. 42 ⫾ 1 ms). However, as shown for comparison purposes in Fig. 4, LV
cardiocytes from dogs with severe mitral regurgitation
(29), albeit at a different temporal but at a similar
pathophysiological point in the progression of heart
failure, showed significant decrements both in the extent and in the velocity of sarcomere shortening.
DISCUSSION
The principal finding of this study is that the contractile function intrinsic to the RV of dogs with longstanding, severe RV volume overloading is normal.
This stands in distinct contrast to our earlier studies of
severe LV volume overloading, wherein intrinsic contractile function was depressed (19, 27, 29). This contrast is all the more striking when one considers that
the dogs with severe mitral regurgitation were studied
at 3–6 mo after the lesion was produced, whereas the
dogs with severe tricuspid regurgitation were studied
at 3.5–4.0 yr after the lesion was produced. Indeed, we
would have preferred to have more dogs available here
for final study, but the fact that contractile function
was normal in tricuspid regurgitation gives us confidence in the validity of our principal finding. That is,
experimental artifacts exaggerated by a low sample
number might well have led to a false finding of abnor-
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Fig. 4. Summary of sarcomere dynamics
in RV cardiocytes from 5 dogs with tricuspid regurgitation (A: Cross-hatched bars)
versus those in RV cardiocytes from 7
control dogs (hatched bars). Also shown
for comparison are summary data taken
from our previous study (see Ref. 29) of
sarcomere dynamics in LV cardiocytes
from 10 dogs with mitral regurgitation
(B: Cross-hatched bars) versus those in
LV cardiocytes from 7 control dogs
(hatched bars). Values are means ⫾ SE.
Statistical comparisons were made by
Student’s unpaired t-test between the
control and experimental group within
each category rather than between the
two categories. *P ⬍ 0.05 for difference
from the respective within-category control group.
MYOCARDIAL FUNCTION IN TRICUSPID REGURGITATION
cuspid than in mitral regurgitation. Thus the attenuated LV hypertrophic response to load in mitral regurgitation may lead by default to an early, sustained
reliance on increases in heart rate and adrenergic tone,
which we have shown to be clearly deleterious to intrinsic myocardial properties in mitral regurgitation
(19, 27) and to intrinsic cardiac cellular properties in
normal isolated cardiocytes (17).
This difference between RV and LV volume overloading may also be related, at least speculatively, to the
following additional factors. First, the initial hemodynamic burden caused by sudden and severe atrioventricular valvular incompetence may be greater when
imposed on the high-systolic-pressure LV than it is
when imposed on the low-systolic-pressure RV. Second,
in the present study of tricuspid regurgitation, LV
function was normal, such that there may have been
less neurohumoral stimulation (12). The renin-angiotensin system and sympathetic nervous system have a
clear role in the development of LV failure after systemic hemodynamic overloads (14), but these systems
could be less important in isolated tricuspid regurgitation in the absence of LV dysfunction. Third, because
LV contraction contributes to the generation of RV
stroke work via the interventricular septum (13, 23),
the normal interventricular septum in tricuspid regurgitation may contribute to the maintenance of overall
RV function.
Clinical experience demonstrates that RV volume
overloading is well tolerated in the absence of pressure
overloading superimposed by pulmonary hypertension
(16, 20). Furthermore, experimental animal models of
arterio-venous fistula (24, 28), atrio-ventricular blockade (21), and atrial septal defect (8) also demonstrate
normal intrinsic RV function in RV volume overloading. In contrast, whereas chronic LV volume overloading in humans may be tolerated for years, LV dysfunction and heart failure often supervene eventually (4, 9,
11, 25, 26), quite possibly related to our finding of
depressed intrinsic LV contractile function in this entity (29). Thus, whereas both RV and LV volume overloading may cause overt heart failure, the preserved
intrinsic RV contractile function shown in this and in
our earlier study (8) of RV volume overloading, and the
exhausted intrinsic LV contractile function shown in
our studies (3, 5, 19, 27, 29) of LV volume overloading,
suggest that the etiology of this heart failure may be
predominantly nonmyocardial in the former case and
myocardial in the latter case.
The authors thank Dr. Robert Bauman for preparing the dogs
with tricuspid regurgitation as well as Gilberto DeFreyte and Mary
Barnes for technical assistance.
This study was supported by National Heart, Lung, and Blood
Institute Grants HL-18468 and HL-48788 and by research funds
from the Department of Veterans Affairs.
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The distinction made evident through the striking
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MYOCARDIAL FUNCTION IN TRICUSPID REGURGITATION
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