Left ventricular hypertrophy due to volume overload versus pressure overload BLASE
A. CARABELLO,
MICHAEL
R. ZILE,
RYUHEI
TANAKA,
AND GEORGE
COOPER
IV
Cardiology Division, Department of Medicine, and the Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, 29425; and Cardiology Section, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29403 Carabello, Blase A., Michael R. Zile, Ryuhei Tanaka, and George Cooper IV. Left ventricular hypertrophy due to volume overload versus pressure overload. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1137-Hl144, 1992.-Left ventricular hemodynamic overload produces an increase in stroke work (SW), which is compensated by the development of left ventricular hypertrophy. However, recent reports question the adequacy of this compensation in mitral regurgitation (MR). Accordingly, we examined the adequacy of compensatory hypertrophy in chronic experimental MR. Six dogs with chronic severe MR were matched according to SW with six dogs that had severe chronic aortic stenosis (AS,,). SW in the two groups was increased identically (40%) compared with normals. However, the hypertrophic response was much greater in the AS group [left ventricular wt (g) to body wt (kg) ratio (LVBW) 4.0 t 0.2 normals, 5.0 t 0.2 MR, and 7.5 t 0.2 AS,,; P < 0.05 MR vs. A&v]. This differing hypertrophic response increased normalized SW, the area within the stress-volume loop, in MR (90 +: 5 g) vs. 63 * 5 g in A& (P < 0.05). Thus in MR, each unit of myocardium had to perform more work than in AS. In a separate comparison, four different dogs with AS (AS,,), which had a similar amount of hypertrophy to the MR dogs (LVBW) (5.0 t 0.2 MR, 5.2 t 0.2 ASHY) were studied. SW was greater in the MR group, suggesting more SW overload was required to produce similar amounts of hypertrophy in MR vs. AS. Contractile function was depressed in the MR group but not in the AS. These findings indicate that the hypertrophic response to a similar SW demand is less in MR than AS, a response associated with contractile dysfunction in the MR group. mitral regurgitation; aortic stenosis OVERLOADS increase ventricular stroke work, the area surrounded by the ventricular pressurevolume loop (Fig. 1A). In pressure overload, stroke work increases because the vertical axis (pressure) of the pressure-volume loop increases. In volume overload, stroke work increases because the horizontal axis (volume) of this loop increases. The chronically increased ventricular stroke work demands of overloaded states are compensated by the development of ventricular hypertrophy (13, 17). Pressure overload results in the development of concentric hypertrophy where parallel sarcomere replication produces increased wall thickness; volume overload results in series sarcomere replication and eccentric hypertrophy. Grossman (17) has hypothesized that in pressure overload, it is increased systolic wall stress, stress = pressure x radius/2 thickness, which triggers the concentric hypertrophic response whereby increased thickness offsets increased pressure, normalizing stress (18). In this manner, afterload on individual muscle fibers remains normal despite high systolic pressure. In volume overload, increased diastolic stress is thought to trigger the eccentric hypertrophic response whereby increased ventricular size permits the ventricle to pump HEMODYNAMIC
increased stroke volume. For complete compensation in volume overload, mass should increase in proportion to volume (thickness should increase in proportion to radius) so that adequate mass is present to pump the extra volume while wall stress remains normal. The magnitude of the hypertrophic response to pressure versus volume overload is controversial. Some reports have indicated that the hypertrophic response is adequate or even exuberant in pressure overload (18, 19, 22, 30, 35) but may be greatest in volume overload (14, 22). Other reports have suggested a limited hypertrophic response in mitral regurgitation (MR) (11, 31, 37) where the increase in left ventricular volume outstrips the increase in ventricular mass. We have noted a limited hypertrophic response in experimental MR (25, 27) where the mass-to-volume ratio in MR is reduced compared with normal. This reduction in the mass to volume ratio in MR could represent an appropriate or inappropriate hypertrophic response. The relative reduction in mass with respect to volume could be an appropriate remodeling of the left ventricle if the pathological pathway for ventricular ejection into the left atrium unloaded the ventricle and reduced overall work requirements despite the presence of volume overload. On the other hand, if stroke work demands were still high despite unloading, the reduced mass-to-volume ratio might indicate an inappropriate, inadequate response, wherein less mass than necessary was present to compensate the increased stroke work demands. If this were the case, it could lead to excess load on the existing myocardium, which might help to explain the muscle dysfunction that is known to develop in chronic experimental MR (6, 27). To help resolve this issue of adequacy of hypertrophy in MR, we compared the hypertrophic response in decompensated MR to that of both compensated and decompensated pressure overload produced by aortic banding. Because the direct comparison between these groups is made difficult by their heterogeneity in hemodynamic response (increased pressure vs. increased volume), we made several types of reinforcing comparisons. First, we compared groups of MR and aortic stenosis (AS) dogs for the overload present by matching the two groups by stroke work. This concept is based on the work of Dodge and Baxley (13), indicating a link between stroke work and the hypertrophic response. We hypothesized that when matched to the amount of overload, we would find less hypertrophy in the MR group to bear the excess load (inadequate hypertrophy). Second, we matched the two types of overload for amount of left ventricular hypertrophy present. We hypothesized that more stroke work overload in the MR group would be required to produce hypertrophy
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H1138
HYPERTROPHY G250 I E g w200
IN VOLUME
A
5 t-i w150 5f a 5100 3 0 E g 50
w > IL LlJ A
O-
0
LEFT
250
20 VENTRICUL
40
60
.AR VOLUME
(ml)
B
-2ooNE 0 ,150; ZlOOE cn
50-
0-
0
20
40
VOLUME
60
80
(c m3)
Fig. 1. A: typical pressure-volume loop developed from echocardiographic and left ventricular pressure data from a dog with aortic stenosis is demonstrated. Stroke work is area within this loop. B: stress-volume loop from a normal subject is demonstrated. Area within this loop represents normalized stroke work.
similar in magnitude to the AS group which, if true, would support the notion that hypertrophic response to overload is less marked in the MR group. Finally, we compared the hypertrophic response in both types of overload in animals in which left ventricular dysfunction had developed. Here, based on previous studies (19), we hypothesized that failure would occur in the AS group only after severe hypertrophy had developed contrasting the differences in the magnitude of hypertrophy present in the two types of overload when dysfunction develops. METHODS
Study design. Five groups of animals were compared: six normal dogs (NL), six dogs with chronic decompensated MR produced by chordal rupture, six dogs with chronic compensated AS produced by aortic banding, matched to the MR dogs according to stroke work (AS,,), four different AS dogs matched to the MR dogs according to the amount of hypertrophy present (AS,,), and three other dogs with decompensated AS matched to MR dogs for the presence of left ventricular dysfunction (AS,,,,). Data were obtained in the lightly sedated but conscious state’3 mo after creation of the lesion using echocardiograms obtained simultaneously with high-fidelity pressure tracings from left ventricular micromanometer catheters. Because it would have been nearly impossible to have prospectively created just enough MR and AS to produce similarly increased stroke work, hypertrophy, or ventricular dysfunction in the overload groups 3 mo later, this study was performed retrospectively. The animals studied were selected from cadres of dogs with MR and AS that were studied in this laboratory over the past two years.
VS. PRESSURE
OVERLOAD
Six dogs with MR were selected at random, hemodynamic and volumetric data analyzed, and stroke work calculated. Then dogs with AS were also analyzed. When a dog with AS was found to have a calculated stroke work within 5% of that of an MR dog, the two animals were matched and so on until six pairs were formed. Nine dogs with AS had to be analyzed to supply the six stroke work matches for the MR dogs. All remaining AS dogs were then examined for the amount of left ventricular hypertrophy present and for the presence of left ventricular dysfunction. Four dogs (different from the ASsw group) with AS had hypertrophy amounts in the range of the MR dogs and formed the ASH, group. Three other AS dogs had left ventricular dysfunction defined as reduced left ventricular fractional shortening and as a mean velocity of circumferential fiber shortening, i.e., end-systolic stress relationship (see below) that was clearly abnormal. These formed the third AS group (AS,,,,). Because of the retrospective nature of the study, other data from some of the animals have been reported in previous studies. In all cases, the previously reported data were angiographic data obtained in the anesthetized, p-blocked dog (6). Our intent in gathering the data presented in this study was to examine ventricular mechanics in the conscious lightly sedated non-bblocked state, since we felt that these conditions would better mimic the hemodynamic situation that produced the stimulus for cardiac hypertrophy than would data obtained during anesthesia. Thus the echocardiographic data presented in this study examining the conscious unblocked state are unique to it; none of the current data has been previously presented. Creation of MR. MR was created in the closed-chest dog by methods previously described (6, 25, 27). Briefly, animals were anesthetized with a combination of fentanyl-droperidol given intravenously and a combination of nitrous-oxide and oxygen given by inhalation. A Swan-Ganz catheter was advanced from an external jugular vein to the pulmonary artery for the purpose of measuring pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output. A 7-Fr 30-cm sheath was then advanced across the aortic valve into the left ventricle. A urological stone-grasping forcep was inserted into the sheath beneath the mitral valve apparatus. The forcep was used to grasp chorda tendineae, forcible retraction of which severed the chordae producing MR. When forward stroke volume (thermodilution) had fallen to 50% of its initial value and pulmonary capillary wedge pressure had risen to 20 mmHg or greater it was presumed that severe MR had been created. At this time the forcep was removed and replaced with a pigtail catheter, which was used to perform left ventricular cineangiography to confirm the severity of MR. The catheters were withdrawn, the wounds closed, and the animals recovered under veterinarian supervision. At all times, standards for animal care met or exceeded those of the American Physiological Society. Creation of AS. Puppies weighing 5-8 kg were banded at 10 wk of age (26). Briefly, after anesthesia was induced with an intravenous injection of droperidol-fentanyl, endotracheal intubation was performed, and the animals were connected to a mechanical respirator. Anesthesia was then provided by the inhalation of isoflurane. A left thoracotomy was performed, and the pericardium was incised. A cutdown was performed on the left femoral artery, and a 6-Fr sheath was inserted into this vessel. The sheath was connected to a previously calibrated fluid-filled transducer. A 5-Fr catheter was attached to a second previously calibrated fluid-filled manometer, passed through the sheath, and with the use of pressure monitoring, the catheter was advanced to the left ventricle. A 5-mm wide mersiline band was then placed around the ascending aorta 2 cm above the coronary arteries. It was tightened and held in place by a right angle clamp until an approximate 20-mm gradient existed between the femoral artery and left ventricle. The ends of the band
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HYPERTROPHY
IN
VOLUME
were then sutured together, the gradient was reconfirmed, and the right angle clamp was removed. The thoracotomy was repaired, and the animals were allowed to recover under veterinarian supervision. As growth occurred, increased cardiac output through the fixed banded stenosis increased the left ventricular pressure and transband gradient serving as a stimulus to pressure overload hypertrophy. Assessment of left ventricular mechanics 3 mo after creation of hemodynamic lesions. Three months after either MR or AS was created, the animals were brought to the experimental cardiac catheterization laboratory while under light anesthesia provided by intravenously administered droperidol-fentanyl. The animals breathed spontaneously. After the right neck was infiltrated with lidocaine for local anesthesia, a small incision was made. The right carotid artery was isolated, and a 5-Fr pigtail catheter was inserted. This catheter was connected to a previously calibrated fluid-filled manometer. Into this same vessel a double-transducer, high-fidelity, micromanometer-tipped catheter was also inserted into the left ventricle. Recordings from both micromanometers were then matched to the fluid-filled pressure tracing. The micromanometer catheter was then pulled back so that one transducer remained in the left ventricle while the other resided in the aorta. In the aortic-banded animals, the proximal transducer was always located proximal to the band. Two-dimensional short- and long-axis echocardiograms of the left ventricle were obtained from the left parasternal and apical positions. These recordings were made simultaneously with pressure recordings from the high-fidelity left ventricular catheter. Data were acquired from six healthy controls in an identical fashion to that used for the animals with MR and AS. Data acquired and calculations made. Left ventricular mass (g), body weight (kg), and the ratio of left ventricular mass to body weight were obtained for each animal. Left ventricular mass was calculated from echocardiographic measurements using the formula (34): LV mass = muscle cross-sectional area (CSA) x long axis dimension, where CSA = r(D/2 + h)2 r(D/2)“, D is left ventricular minor axis, and h is wall thickness. We have previously demonstrated an excellent correlation between echocardiographically calculated mass using the technique and actual weighed left ventricular mass made at autopsy (24, 34, 38). Left ventricular volumes (v) were calculated from the echocardiograms using the formula V =-
TD 2L 6
where L is left ventricular long-axis dimension. Left ventricular circumferential wall stress was calculated using the simultaneously recorded pressure, volume, dimension, and wall thickness data. The formula used to calculate stress was (28) (P L . D) h(2L + 0.8D + 1.6h) ’ 1*33*g-1*cm-”
VS. PRESSURE
H1139
OVERLOAD
was defined as the largest left ventricular volume during the cardiac cycle. E&l systole was defined from pressure data as the point in time where the dicrotic notch occurred and from the synchronized echocardiographic data corresponding to this point. Although the precise definition of end systole may be difficult in MR (4), these points were chosen because of their exact definition and correlation with time-varying elastance, a more precise way of defining end systole (27,33). Mean systolic stress was calculated as time-varying stress averaged over the time from the beginning of the left ventricular upstroke to the dicrotic notch as shown in Fig. 2. Assessment of hemodynamic lesions 3 mo after lesion creation. The severity of AS was assessed as the peak systolic gradient between the left ventricle and ascending aorta distal to the band. To assess the severity of MR, a slightly deeper plane of anesthesia was provided by injection of intravenous droperidolfentanyl after the echocardiographic data had been obtained. A thermodilution Swan-Ganz catheter was advanced from the right jugular vein to the pulmonary artery for the purpose of measuring forward cardiac output. Contrast tine left ventriculography was performed in the right anterior oblique position. Cineangiographic left ventricular stroke volume (total stroke volume) and forward stroke volume (thermodilution cardiac output/heart rate) were used to calculate regurgitant fraction using the formula: regurgitant fraction = total stroke volume forward stroke volume/total stroke volume. This method has been previously validated in our laboratory (6,27). Left ventricular function was assessed using the relationship between mean velocity of circumferential fiber shortening ( VCF) and end-systolic wall stress (6, 8, 12). This relationship assesses contractile function by correcting an afterload-sensitive ejection phase inand its 95% confidence dex, VW, for afterload. The relationship limits were developed from eight normal subjects against which the animals with hypertrophy were then plotted. The VCF was calculated as V CF=
EDD - ESD EDD ET l
where EDD is end-diastolic dimension, ESD is end-systolic dimension, and ET is ejection time. ET was determined from the beginning of minor axis shortening on the echocardiogram to the dicrotic notch of the aortic pressure tracing. This definition of ET was used to account for the fact that in MR substantial ejection occurs before aortic valve opening but little occurs after aortic valve closure (15). Statistics. When the five groups of subjects were compared, analysis of variance was used to detect differences among the groups. If a difference was found to exist, a Newman-Keuls test
l
where P is left ventricular pressure. Left ventricular pressures were digitized, and pressure data were retrieved at 5-ms intervals. These data were then synchronized in time to the appropriate echocardiographic data. The frame rate for our two-dimensional echocardiograms was 30 frames/s. Pressure-volume and stress-volume loops were then developed from these data. Stroke work (SW) is the area within the pressure-volume loop (Fig. 1A). Mathematically it is described as SW = J Pdv. The integral was obtained from the digitized pressure volume data with the aid of a computer. We then multiplied this integral by 0.0136 to convert from millimeters of Hg for expression in the standard units, gram. meters. Stroke work normalized for the myocardium present was calculated as the area within the stress-volume loop as shown in Fig. 1B. End-diastolic volume
;200 E 0 -ml50 -
z
w100 E cn
50
0 60
TIME Fig. 2. Time-varying systolic stress from gitation is demonstrated. Stress averaged systolic stress (118 g/cm”).
(ms) an animal over time
with mitral regurof systole is mean
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H1140
HYPERTROPHY
IN VOLUME
was performed to find where the differences were located. Regression analysis using the least squares technique was used to develop the VcF- stress relationship. Dispersion from the mean is noted as means t SE. RESULTS
Severity of disease. The animals with volume overload had severe MR with an average regurgitant fraction of 0.62 t 0.02. Th e 1eft ventricular peak systolic pressure in the ASH, group was 160 t 12 mmHg. This was significantly less (P < 0.05) than the peak left ventricular systolic pressures in the ASsw group (212 t 16 mmHg) or the ASDys g roup (220 t 25 mmHg). Left uentricular hypertrophy. Left ventricular mass was evaluated in relationship to body weight and is described as the ratio of left ventricular weight (g) to body weight (kg) (LVBW). As shown in Fig. 3, the LVBW was significantly elevated compared with normals in all the experimental groups. The LVBW was similar in the MR and the ASH, groups by design. This ratio was significantly higher in the AS sw group than either the MR or the ASH, groups (P < 0.05). The LVBW was significantly higher (P < 0.05) in the ASpYs group than all other groups. The ratio of mass to volume was depressed in the MR group (1.13 t 0.05) compared with normal (1.65 t 0.15; 11
n
10
:i
9 A
VS. PRESSURE
P < O.Ol), with ASH, (2.03 t 0.06; P < O.Ol), with ASsw (2.46 + 0.20; P c O.OOl), and with ASpys (1.84 t 0.35; P = 0.02). The ratio was increased in the ASsw compared with normal (P < 0.05). Stroke work. Stroke work for the five groups is shown in Fig. 4. Stroke work was significantly elevated compared with normal in the MR and ASsw groups (P < 0.01). By design the MR and ASsw groups were matched to be equal. Pressure volume loops (the area enclosed by which is stroke work) are demonstrated for the matched pairs of MR and AS sw dogs in Fig. 5. While the areas are matched to be equal, the shapes are quite different. Comparison of stroke work between the MR and ASH, groups, which were matched for hypertrophy, shows that the stroke work associated with this amount of hypertrophy was less in the ASH, group than the MR group (P < 0.05). Thus similar amounts of hypertrophy in the ASH, and MR groups were associated with less stroke work in the ASH, group than the MR group. Normdized stroke work. Normalized stroke work (the area within the stress-volume loop) is demonstrated for the five groups in Fig. 6. Normalized stroke work was not different among normals and in the ASsw and ASH, groups, although it tended to be higher in ASsw group. Normalized stroke work was significantly elevated (P C 0.01) in the MR group and in the ASDys group, the two groups with decompensated left ventricular function. Left ventricular function. Figure 7 demonstrates the relationship of the mean velocity of circumferential fiber shortening ( VCF) and end-systolic stress in the five groups of animals. Five of the six animals with MR and all of the A& animals fell down and to the left of the normal relationship, indicating reduced velocity of shortening for any given afterload, which suggested impairment of contractile function. WalZ stress. Figure 8 demonstrates end-diastolic and mean systolic wall stress for the experimental groups. End-diastolic stress was elevated in the MR, A&w, and AS pYs groups. Mean systolic stress was elevated only in the AS Dys group*
100
4
OVERLOAD
-
80 -
R (D
8
3 NL
MR *
AShy *
*%v * t+
*‘dys * t+s
Fig. 3. Ratio of left ventricular weight (LV) to body weight (in g/kg) is demonstrated for normal subjects (NL), subjects with mitral regurgitation (MR), subjects matched to have similar aortic stenosis hypertrophy to MR group (AS,,), AS subjects matched to MR group to have similar stroke work (AS,,), and subjects with AS and left ventricular dysfunction (AS,,,). Statistics are demonstrated beneath group labels. * P < 0.05 vs. control, t P < 0.05 vs. MR, $ P c 0.05 vs. ASHy, and Q P c 0.05 vs. AS SW. Ratio was increased in all experimental groups indicating presence of left ventricular hypertrophy. However, when MR and AS groups were matched for stroke work, ASsw had significantly more hypertrophy than MR group. The most hypertrophy was seen in ASyS grow.
20 -
0 NL
MR
AS
*
t
hY
ASsw *+
ASdys
Fig. 4. Stroke work is demonstrated for all five groups. Abbreviations and statistical analysis are same as in previous figure. ASH, group, which was matched to have same amount of hypertrophy as MR group, produced significantly less stroke work than did MR group.
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HYPERTROPHY
N VOLUME
VS. PRESSURE
H1141
OVERLOAD
cl 1
0
a a I 3 0
a -
300
40
120
160
300
cl4
300
cl5
cl6 .
9.
l
200
‘9 . .’
F z
200
.
9 ’
200
.
b b . l 63
‘9 a .
. . . a
100 a 0 a 0 . .
t
W A
.*
. .
.
:
100
’ .
0
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W >
00
86
. ..-•
o-
Ts.
0
)
40
80
120
160
0 0
40
80
LEFT VENTRICULAR Fig. 5. Pressure-volume loops are demonstrated loops (stroke work) were matched to be nearly
for MR identical,
120
160
0
VOLUME
A*,
T
nt
160
by
-O-
\*.
8
120
(ml)
group and for AS sw groups. Although areas surrounded the difference in shape of loops is quite obvious. 2.5
0
80
40
**
CONTROL X
MITRAL
REGURGITATION
0
AORTIC
STENOSIS
(HY)
A
AORTIC
STENOSIS
(SW)
STENOSIS
(DYS)
X
1
OJ
NL
MR *
AShy
t
ASsw
t
*xsdys
Fig. 6. Normalized stroke work (area surrounded by stress-volume loop) is shown for five groups. Abbreviations and statistical analysis are same as shown for previous figures. In two groups with dysfunction (MR, AS&, normalized stroke work was significantly greater than normal. In other two compensated AS groups, normalized stroke work was not greater than normal and was less than MR groups. DISCUSSION
Comparison of pressure overload hypertrophy to volume overload hypertrophy is made difficult by the differences in the hemodynamic variables between the two types of overload. The current study helps to circumvent this problem by matching the lesions at various points of commonality. This study demonstrated that the hypertrophic response to the volume overload of MR was less than the hypertrophic response to pressure overload. This conclusion is based on three findings. First, when matched by stroke work, the chronic volume overload of experimental MR produced less left ventricular hypertro-
1 60
80
END
1
I
1
1
I
I
100
120
140
160
180
200
SYSTOLIC
STRESS
(gm/cm2)
Fig. 7. Relationship of mean velocity of circumferential fiber shortening (I&) vs. end-systolic stress and confidence limits for normal subjects is demonstrated. Five of the six MR dogs and all of the ASnys dogs fell down and the left of this relationship indicating impaired contractile function.
phy than did equal stroke work produced by the chronic pressure overload of experimental AS. Second, when MR and AS dogs were matched for the amount of hypertrophy present, the stroke work associated with this amount of hypertrophy was greater in the MR group than the ASH, group, suggesting that more overload in volume versus pressure overload was required to produce the same amount of hypertrophy. Finally, in both the decompensated groups (MR and AS,,,), normalized stroke work was elevated, indicating that each unit of myocardium had to perform more work than normals or the compensated AS groups. Thus in both cases the hvpertrophv was
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Hl142
HYPERTROPHY 100 90 80
IN VOLUME
1 A
1 X
NE 60 x50
0 0 %
0j
- B : : : : : : : -
n n
iid
n
T
i
A
A
0
Cl MR *
NL
320 300 280 260 240 220 200 "E 180 -9 160 ;140: v,120=1001 80 60 40 20
A
AS
AS
ASsw *
hY
* dYS
A X
m 4
: : : : 0' NL
MR
AShy
ASsw
ASdys
*t9 Fig. 8. A: end-diastolic stress (EDS) is demonstrated for the five groups. B: mean systolic stress (MSS) is demonstrated for the five groups. Mean systolic stress was elevated only in the ASijys group. Abbreviations and statistical analysis are same as shown for previous figures.
inadequate to norma lize stroke work per unit of myocardium. Howeve lr, this normalization failed to occur in MR becau se only a modest amount of hypertrophy had d.evelOPd whereas in AS the hypertrophy was extreme. This dichotomy suggests two different explanations for the inadequate hypertrophic response, when it occurred, in the two diseases. In MR the relatively small amount of hypertrophy present suggests that the hypertrophic response failed to be induced. In the A& group, the extreme hypertrophy present suggests that some biological limit of hypertrophy might have been reached beyond which hypertrophic compensation was impossible (19). In the ASDys dogs and in five of the six MR dogs these changes were also associated with a deficit in contractile function, which did not occur in nine of the 10 other AS animals. Whether the increased normalized stroke work in MR and the ASDys dogs and the contractile deficit are causally related cannot be stated definitively from our results. We postulate however that there may be cause and effect, since hemodynamic overload is generally considered responsible for muscle dysfunction in overload states (3, 10, 20, 32). While previous studies of pressure overload have shown that severe left ventricular hypertrophy as is present in our A& group is associated with left ventricular dysfunction (16, 23), the current study further suggests that inadequate hypertrophy in volume
VS. PRESSURE
OVERLOAD
overload also may occur and lead to ventricular dysfunction but at much less severe degree of hypertrophy. Consistent with our finding of increased normalized stroke work in MR is the finding that the mass-to-volume ratio was depressed in this model. Thus there was less mass present relative to the volume being pumped. In all of our previous investigations of experimental MR, the mass-to-volume ratio and/or the of wall thickness-toradius (which is concordant with mass and volume changes) was also depressed in animals with decompensated left ventricular function (6,25,27). Our finding of a reduced mass-to-volume ratio in experimental MR is in agreement with reports concerning this lesion in humans. Corin et al. (11) in an angiographic study of humans found mass index to volume index was 1.03 in normal subjects but was reduced to 0.70 in patients with MR. Schuler et al. (31) used echocardiography to study left ventricular mass and geometry in patients with MR. Reanalysis of their data revealed an estimated mass-tovolume ratio of 1.52 in patients with compensated MR but only 0.91 in those patients with decompensated MR. Likewise, Wong and Spotnitz (37) found a mass-tovolume ratio of 1.52 in patients with coronary disease and normal left ventricles; this ratio was depressed to 1.19 in patients with MR. If the hypertrophy that developed in the MR group is truly inadequate, the question remains why fully compensatory hypertrophy failed to occur. Unlike the severe hypertrophy in the A& group where a biological limit to the hypertrophy could have been met, the hypertrophy in the MR groups was relatively mild. Why more hypertrophy did not develop is unclear. The stimulus for hypertrophy is proposed to be systolic and diastolic wall stress (18). Acute MR leads to a depression in systolic wall stress (27), which could theoretically cause a reduction in muscle mass, since the stimulus for maintaining muscle mass is reduced. With time, chamber dilatation increases the radius term in the stress equation thereby increasing systolic wall stress to normal as it was in this study. However, only when ejection performance is severely depressed in MR does systolic wall stress become higher than normal (11) where it might serve as a stimulus to hypertrophy. While diastolic stress was elevated in the animals with MR, previous investigations have suggested that diastolic stress is a less effective stimulus to hypertrophy than systolic stress (18, 21, 29). Thus it may be that increased diastolic stress in the face of normal systolic stress leads to only mild hypertrophy in MR. This differs from aortic regurgitation where both systolic and diastolic wall stress are increased (36) and the hypertrophic response is generous. In support of this concept, reanalysis of Grossman’s et al. (18) original data regarding hypertrophy in humans found the ratio of thickness to radius in MR to be 0.29 t 0.02, which was significantly less than that seen in aortic regurgitation (0.38 t 0.03). The above discussion focuses on differences in load between MR and aortic banding as the key determinants of the hypertrophic response and its adequacy. However, differences in neurohumoral mechanisms between the two models may also have been operative and could help
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HYPERTROPHY
IN VOLUME
explain differences in modulation of the hypertrophic response (9). Our study was not designed to assess these influences. Regardless of the mechanism involved, the result was that there was relatively less ventricular muscle mass to meet stroke work demands in animals with MR compared with normals or animals with AS. MR is probably exceptional in leading to this sort of hypertrophic response, since it is the only common low pressure (“pure”) volume overload where the excess volume pumped is ejected into the relatively low pressure of the left atrium (6). In other types of left ventricular volume overload such as anemia, aortic regurgitation, heart block, etc., the excess volume is ejected into the higher pressure of the aorta. Limitations. It should be noted that pressure overload hypertrophy was induced in young dogs, whereas volume overload hypertrophy was induced in adults. Quantitative and qualitative differences between the young heart, which is developing both physiological (growth) hypertrophy and pathological hypertrophy, and the adult heart experiencing only pathological hypertrophy could exist. Our study cannot directly address this question. However, adult dogs experiencing pressure overload from valve plication performed in adulthood can develop a similar amount of hypertrophy to our younger group (1). Thus the magnitude of hypertrophy seen in our younger pressure overload group cannot be explained simply by the young age, since pressure overloaded adults can also develop a similar amount of hypertrophy. Thus the difference in the type of load between MR and AS rather than the difference in age is the likely explanation for our results. Furthermore, Bathe et al. (2) found no differences with respect to coronary blood flow in adult versus juvenile animals with pressure overload hypertrophy, suggesting that at least this feature of hypertrophy is not different between adults and juveniles. Another concern regarding the variation in age among our groups is whether the ratio of left ventricular weight to body weight varies with age. If it did, our adult control group might not be a fair standard against which to judge the younger animals. However, this ratio has been reported to be 3.9 t 0.14 in 7- to 8-mo-old dogs similar in age (6 mo) to the dogs reported here and nearly identical to the value for the current adult controls (5). Thus left ventricular weight/body weight seems a fair reference for comparison of the amount of hypertrophy between the groups. A second potential cause for the discrepancy in the hypertrophy between the two models is the acuteness of the overload in the MR group versus the more chronically imposed overload in the AS group. We can only speculate about what difference this might cause. However, we believe the models employed remain relevant in this regard, since many pathological volume overloads (valvular endocarditis, chordal rupture, papillary muscle dysfunction) occur acutely compared with most pressure overloads, which develop more chronically. Contractile function in this study was assessed using the mean VcF-stress relationship (6, 8, 12). The imprecision in defining end systole in MR could lead to inaccuracy of this method in that group of dogs. However, our
VS. PRESSURE
H1143
OVERLOAD
conclusion that contractile function was depressed in MR using this technique is identical to our assessment of contractile function in MR in previous studies using more accurate and sophisticated techniques (6, 7,27). Thus we probably judged contractile function accurately when we found it was depressed in MR and ASDys animals in this study. Finally, we acknowledge that retrospective analysis is always fraught with potential bias. However, we believe that random selection of the MR dogs followed by consecutive matching with the AS dogs helped to mitigate methodological bias. In conclusion, volume overload induced by MR produced strikingly less left ventricular hypertrophy than did a stroke work-matched pressure overload. In MR the hypertrophy was inadequate to normalize stroke work per unit of myocardium, a feature in turn associated with contractile dysfunction. Inadequate hypertrophy also occurred in some subjects with pressure overload. However, while the hypertrophy in these pressure overload subjects was inadequate to normalize stroke work per unit of myocardium, the amount of hypertrophy was extreme, unlike in MR where it was mild. These data suggest that in MR, inadequacy of hypertrophy results from failure of the hypertrophy to be induced while in pressure overload, inadequacy may result when some biological limit to hypertrophy is met. This research was supported in part by the Research Service of the Dept. of Veterans Affairs, Washington, D.C. (to M. R. Zile, G. Cooper IV, and B. A. Carabello) and by a National Heart, Lung, Blood Institute Grant ROl-HL-38185 (to B. A. Carabello). Address for reprint requests: B. A. Carabello, Cardiology Division, Medical Univ. of South Carolina, 171 Ashley Ave., Charleston, SC 294252221. Received
30 October
1991; accepted
in final
form
2 June
1992.
REFERENCES 1. Allard,
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J. R., M. J. O’Neill, and J. I. E. Hoffman. Valvular subcoronary aortic stenosis in dogs. Am. J. Physiol. 236 (Heart Circ. Physiol. 5): H780-H784, 1979. Bathe, R. J., D. Alyono, E. Sublett, and X.-Z. Dai. Myocardial blood flow in left ventricular hypertrophy developing in young and adult dogs. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H949-H956, 1986. Bonow, R. O., A. L. Picone, C. L. McIntosh, M. Jones, D. R. Rosing, B. J. Maron, E. Lakatos, R. E. Clark, and S. E. Epstein. Survival and functional results after valve replacement for aortic regurgitation from 1976 to 1983: impact of preoperative left ventricular function. Circulation 72: 1244-1256, 1985. Brickner, M. E., and M. R. Starling. Dissociation of end systole from end ejection in patients with long-term mitral regurgitation. Circulation 81: 1277-1286, 1990. Carabello, B. A., R. Mee, J. J. Collins, Jr., R. A. Kloner, D. Levin, and W. Grossman. Contractile function in chronic gradually developing subcoronary aortic stenosis. Am. J. Physiol. 240 (Heart Circ. Physiol. 9): H80-H86, 1981. Carabello, B. A., K. Nakano, W. Corin, R. Biederman, and J. F. Spann, Jr. Left ventricular function in experimental volume overload hypertrophy. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H974-H981, 1989. Carabello, B. A., K. Nakano, K. Ishihara, S. Kanazawa, R. W. W. Biederman, and J. F. Spann, Jr. Coronary blood flow in dogs with contractile dysfunction due to experimental volume overload. Circulation 83: 1063-1075, 1991. Colan, S. D., K. M. Borow, and A. Neumann. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load-independent index of myocardial contractility. J. Am. Coil.
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Cardiol. 4: 715-724, 1984. 9. Cooper, G. Cardiocyte adaptation to chronically altered load. Annu. Rev. Physiol. 49: 501-518, 1987. 10. Cooper, G., IV, R. J. Tomanek, 3. C. Ehrhardt, and M. L. Marcus. Chronic progressive pressure overload of the cat right ventricle. Circ. Res. 48: 488-497, 1981. 11. Corin, W. J., E. S. Monrad, T. Murakami, H. Nonogi, 0. M. Hess, and H. P. Krayenbuehl. The relationship of afterload to ejection performance in chronic mitral regurgitation. Circulation 76: 59-67, 1987. 12. Corin, W. J., M. M. Swindle, J. F. Spann, K. Nakano, M. Frankis, R. W. Biederman, A. Smith, A. Taylor, and B. A. Carabello. Mechanism of decreased forward stroke volume in children and swine with ventricular septal defect and failure to thrive. J. Clin. Invest. 82: 544-551, 1988. 13. Dodge, H. T., and W. A. Baxley. Left ventricular volume and mass and their significance in heart disease. Am. J. Cardiol. 23: 528-537, 1969. 14. Dodge, H. T., J. W. Kennedy, and J. L. Petersen. Quantitative angiocardiographic methods i,n the evaluation of valvular heart disease. Prog. Cardiovasc. Dis. 16: l-23, 1973. 15. Eckberg, D. L., J. H. Gault, R. L. Bowchard, J. S. Karliner, and J. Ross, Jr. Mechanics of left ventricular contraction in chronic severe mitral regurgitation. Circulation 47: 1252-1259, 1973. 16. Fujii, A. M., R. J. Gelpi, I. Mirsky, and S. F. Vatner. Systolic and diastolic dysfunction during atria1 pacing in conscious dogs with left ventricular hypertrophy. Circ. Res. 62: 462-470, 1988. 17. Grossman, W. Cardiac hypertrophy: useful adaptation or pathologic process? Am. J. Med. 69: 576-584, 1980. 18. Grossman, W., D. Jones, and L. P. McLaurin. Wall stress and patterns of hypertrophy in the human left ventricle. J. Clin. Invest. 56: 56-64, 1974. 19. Gunther, S., and W. Grossman. Determinants of ventricular function in pressure-overload hypertrophy in man. Circulation 59: 679-688, 1979. 20. Hildner, F. J., R. P. Javier, L. S. Cohen, P. Samet, M. J. Nathan, W. 2. Yahr, and J. J. Greenberg. Myocardial dysfunction associated with valvular heart disease. Am. J. Cardiol. 30: 319326, 1972. 21. Hjalmarson, A., and 0. Isaksson. In vitro work load and rate heart metabolism. I. Effect on protein synthesis. Acta Physiol. Stand. 86: 126-144, 1972. 22. Hood, W. P., C. E. Rackley, and E. L. Rolett. Wall stress in the normal and hypertrophied human left ventricle. Am. J. Cardiol. 22: 550-558, 1968. 23. Huber, D., J. Grimm, R. Koch, and H. P. Krayenbuehl. Determinants of ejection performance in aortic stenosis. Circulation 64: 126-134, 1981. 24. Ishihara, K., M. R. Zile, M. Tomita, R. Tanaka, S. Kanazawa, and B. A. Carabello. Left ventricular hypertrophy in a canine model of reversible pressure overload. Cardiovasc. Res. 26: 580-585, 1992. 25. Kleaveland, J. P., W. G. Kussmaul, T. Vinciguerra, R. Diters, and B. A. Carabello. Volume overload hypertrophy
VS. PRESSURE
26.
27.
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38.
OVERLOAD
in a closed-chest model of mitral regurgitation. Am. J. Physiol. 254 (Heart Circ. Physkl. 23): H1034H1041, 1988. Nakano, K., W. J. Corin, J. F. Spann, Jr., R. W. W. Biederman, S. Denslow, and B. A. Carabello. Abnormal subendocardial blood flow in pressure overload hypertrophy is associated with pacing-induced subendocardial dysfunction. Circ. Res. 65: 1555- 1564, 1989. Nakano, K., M. M. Swindle, F. Spinale, K. Ishihara, S. Kanazawa, A. Smith, R. W. W. Biederman, L. Clamp, Y. Hamada, M. R. Zile, and B. A. Carabello. Depressed contractile function due to canine mitral regurgitation improves following correction of the volume overload. J. Clin. Invest. 87: 20772086, 1991. Pasipoularides, A., I. Mirsky, 0. M. Hess, J. Grimm, and H. P. Krayenbuehl. Myocardial relaxation and passive diastolic properties in man. Circulation 74: 991-1001, 1986. Peterson, M. B., and M. Lesch. Protein synthesis and amino acid transport in the isolated rabbit right ventricular papillary muscle. Circ. Res. 31: 317-327, 1972. Sasayama, S., D. Franklin, and J. Ross, Jr. Hyperfunction with normal inotropic state of the hypertrophied left ventricle. Am. J. Physiol. 232 (Heart Circ. Physiol. 1): H418-H425, 1977. Schuler, G., K. L. Peterson, A. Johnson, G. Francis, G. Dennish, J. Utley, P. 0. Daily, W. Ashburn, and J. Ross, Jr. Temporal response of left ventricular performance to mitral valve surgery. Circulation 59: 1218-1231, 1979. Spann, J. F., Jr., B. A. Buccino, E. H. Sonnenblick, and E. Braunwald. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circ. Res. 21: 341-354, 1967. Starling, M. R., R. A. Walsh, L. J. Dell’Italia, G. B. J. Mancini, J. C. Lasher, and J. L. Lancaster. The relationship of various measures of end-systole to left ventricular maximum time-varying elastance in man. Circulation 76: 32-43, 1987. Tomita, M., F. G. Spinale, F. A. Crawford, and M. R. Zile. Changes in left ventricular volume, mass, and function during the development and regression of supraventricular tachycardia-induced cardiomyopathy. Disparity between recovery of systolic versus diastolic function. Circulation 83: 635-644, 1991. Wisenbaugh, T., P. Allen, G. Cooper IV, H. Holzgrefe, G. Beller, and B. Carabello. Contractile function, myosin ATPase activity and isozymes in the hypertrophied pig left ventricle after a chronic progressive pressure overload. Circ. Res. 53: 332-341, 1983. Wisenbaugh, T., J. F. Spann, and B. A. Carabello. Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J. Am. Coll. Cardiol. 3: 916-923, 1984. Wong, C. Y. H., and H. M. Spotnitz. Systolic and diastolic properties of the human left ventricle during valve replacement for chronic mitral regurgitation. Am. J. Cardiol. 47: 40-50, 1981. Zile, M. R., M. Tomita, K. Nakano, I. Mirsky, B. Usher, J. Lindroth, and B. A. Carabello. Effects of left ventricular volume overload produced by mitral regurgitation on diastolic function. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1471H1480, 1991.
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A. CARABELLO,
MICHAEL
R. ZILE,
RYUHEI
TANAKA,
AND GEORGE
COOPER
IV
Cardiology Division, Department of Medicine, and the Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, 29425; and Cardiology Section, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29403 Carabello, Blase A., Michael R. Zile, Ryuhei Tanaka, and George Cooper IV. Left ventricular hypertrophy due to volume overload versus pressure overload. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1137-Hl144, 1992.-Left ventricular hemodynamic overload produces an increase in stroke work (SW), which is compensated by the development of left ventricular hypertrophy. However, recent reports question the adequacy of this compensation in mitral regurgitation (MR). Accordingly, we examined the adequacy of compensatory hypertrophy in chronic experimental MR. Six dogs with chronic severe MR were matched according to SW with six dogs that had severe chronic aortic stenosis (AS,,). SW in the two groups was increased identically (40%) compared with normals. However, the hypertrophic response was much greater in the AS group [left ventricular wt (g) to body wt (kg) ratio (LVBW) 4.0 t 0.2 normals, 5.0 t 0.2 MR, and 7.5 t 0.2 AS,,; P < 0.05 MR vs. A&v]. This differing hypertrophic response increased normalized SW, the area within the stress-volume loop, in MR (90 +: 5 g) vs. 63 * 5 g in A& (P < 0.05). Thus in MR, each unit of myocardium had to perform more work than in AS. In a separate comparison, four different dogs with AS (AS,,), which had a similar amount of hypertrophy to the MR dogs (LVBW) (5.0 t 0.2 MR, 5.2 t 0.2 ASHY) were studied. SW was greater in the MR group, suggesting more SW overload was required to produce similar amounts of hypertrophy in MR vs. AS. Contractile function was depressed in the MR group but not in the AS. These findings indicate that the hypertrophic response to a similar SW demand is less in MR than AS, a response associated with contractile dysfunction in the MR group. mitral regurgitation; aortic stenosis OVERLOADS increase ventricular stroke work, the area surrounded by the ventricular pressurevolume loop (Fig. 1A). In pressure overload, stroke work increases because the vertical axis (pressure) of the pressure-volume loop increases. In volume overload, stroke work increases because the horizontal axis (volume) of this loop increases. The chronically increased ventricular stroke work demands of overloaded states are compensated by the development of ventricular hypertrophy (13, 17). Pressure overload results in the development of concentric hypertrophy where parallel sarcomere replication produces increased wall thickness; volume overload results in series sarcomere replication and eccentric hypertrophy. Grossman (17) has hypothesized that in pressure overload, it is increased systolic wall stress, stress = pressure x radius/2 thickness, which triggers the concentric hypertrophic response whereby increased thickness offsets increased pressure, normalizing stress (18). In this manner, afterload on individual muscle fibers remains normal despite high systolic pressure. In volume overload, increased diastolic stress is thought to trigger the eccentric hypertrophic response whereby increased ventricular size permits the ventricle to pump HEMODYNAMIC
increased stroke volume. For complete compensation in volume overload, mass should increase in proportion to volume (thickness should increase in proportion to radius) so that adequate mass is present to pump the extra volume while wall stress remains normal. The magnitude of the hypertrophic response to pressure versus volume overload is controversial. Some reports have indicated that the hypertrophic response is adequate or even exuberant in pressure overload (18, 19, 22, 30, 35) but may be greatest in volume overload (14, 22). Other reports have suggested a limited hypertrophic response in mitral regurgitation (MR) (11, 31, 37) where the increase in left ventricular volume outstrips the increase in ventricular mass. We have noted a limited hypertrophic response in experimental MR (25, 27) where the mass-to-volume ratio in MR is reduced compared with normal. This reduction in the mass to volume ratio in MR could represent an appropriate or inappropriate hypertrophic response. The relative reduction in mass with respect to volume could be an appropriate remodeling of the left ventricle if the pathological pathway for ventricular ejection into the left atrium unloaded the ventricle and reduced overall work requirements despite the presence of volume overload. On the other hand, if stroke work demands were still high despite unloading, the reduced mass-to-volume ratio might indicate an inappropriate, inadequate response, wherein less mass than necessary was present to compensate the increased stroke work demands. If this were the case, it could lead to excess load on the existing myocardium, which might help to explain the muscle dysfunction that is known to develop in chronic experimental MR (6, 27). To help resolve this issue of adequacy of hypertrophy in MR, we compared the hypertrophic response in decompensated MR to that of both compensated and decompensated pressure overload produced by aortic banding. Because the direct comparison between these groups is made difficult by their heterogeneity in hemodynamic response (increased pressure vs. increased volume), we made several types of reinforcing comparisons. First, we compared groups of MR and aortic stenosis (AS) dogs for the overload present by matching the two groups by stroke work. This concept is based on the work of Dodge and Baxley (13), indicating a link between stroke work and the hypertrophic response. We hypothesized that when matched to the amount of overload, we would find less hypertrophy in the MR group to bear the excess load (inadequate hypertrophy). Second, we matched the two types of overload for amount of left ventricular hypertrophy present. We hypothesized that more stroke work overload in the MR group would be required to produce hypertrophy
H1137 Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 9, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
H1138
HYPERTROPHY G250 I E g w200
IN VOLUME
A
5 t-i w150 5f a 5100 3 0 E g 50
w > IL LlJ A
O-
0
LEFT
250
20 VENTRICUL
40
60
.AR VOLUME
(ml)
B
-2ooNE 0 ,150; ZlOOE cn
50-
0-
0
20
40
VOLUME
60
80
(c m3)
Fig. 1. A: typical pressure-volume loop developed from echocardiographic and left ventricular pressure data from a dog with aortic stenosis is demonstrated. Stroke work is area within this loop. B: stress-volume loop from a normal subject is demonstrated. Area within this loop represents normalized stroke work.
similar in magnitude to the AS group which, if true, would support the notion that hypertrophic response to overload is less marked in the MR group. Finally, we compared the hypertrophic response in both types of overload in animals in which left ventricular dysfunction had developed. Here, based on previous studies (19), we hypothesized that failure would occur in the AS group only after severe hypertrophy had developed contrasting the differences in the magnitude of hypertrophy present in the two types of overload when dysfunction develops. METHODS
Study design. Five groups of animals were compared: six normal dogs (NL), six dogs with chronic decompensated MR produced by chordal rupture, six dogs with chronic compensated AS produced by aortic banding, matched to the MR dogs according to stroke work (AS,,), four different AS dogs matched to the MR dogs according to the amount of hypertrophy present (AS,,), and three other dogs with decompensated AS matched to MR dogs for the presence of left ventricular dysfunction (AS,,,,). Data were obtained in the lightly sedated but conscious state’3 mo after creation of the lesion using echocardiograms obtained simultaneously with high-fidelity pressure tracings from left ventricular micromanometer catheters. Because it would have been nearly impossible to have prospectively created just enough MR and AS to produce similarly increased stroke work, hypertrophy, or ventricular dysfunction in the overload groups 3 mo later, this study was performed retrospectively. The animals studied were selected from cadres of dogs with MR and AS that were studied in this laboratory over the past two years.
VS. PRESSURE
OVERLOAD
Six dogs with MR were selected at random, hemodynamic and volumetric data analyzed, and stroke work calculated. Then dogs with AS were also analyzed. When a dog with AS was found to have a calculated stroke work within 5% of that of an MR dog, the two animals were matched and so on until six pairs were formed. Nine dogs with AS had to be analyzed to supply the six stroke work matches for the MR dogs. All remaining AS dogs were then examined for the amount of left ventricular hypertrophy present and for the presence of left ventricular dysfunction. Four dogs (different from the ASsw group) with AS had hypertrophy amounts in the range of the MR dogs and formed the ASH, group. Three other AS dogs had left ventricular dysfunction defined as reduced left ventricular fractional shortening and as a mean velocity of circumferential fiber shortening, i.e., end-systolic stress relationship (see below) that was clearly abnormal. These formed the third AS group (AS,,,,). Because of the retrospective nature of the study, other data from some of the animals have been reported in previous studies. In all cases, the previously reported data were angiographic data obtained in the anesthetized, p-blocked dog (6). Our intent in gathering the data presented in this study was to examine ventricular mechanics in the conscious lightly sedated non-bblocked state, since we felt that these conditions would better mimic the hemodynamic situation that produced the stimulus for cardiac hypertrophy than would data obtained during anesthesia. Thus the echocardiographic data presented in this study examining the conscious unblocked state are unique to it; none of the current data has been previously presented. Creation of MR. MR was created in the closed-chest dog by methods previously described (6, 25, 27). Briefly, animals were anesthetized with a combination of fentanyl-droperidol given intravenously and a combination of nitrous-oxide and oxygen given by inhalation. A Swan-Ganz catheter was advanced from an external jugular vein to the pulmonary artery for the purpose of measuring pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output. A 7-Fr 30-cm sheath was then advanced across the aortic valve into the left ventricle. A urological stone-grasping forcep was inserted into the sheath beneath the mitral valve apparatus. The forcep was used to grasp chorda tendineae, forcible retraction of which severed the chordae producing MR. When forward stroke volume (thermodilution) had fallen to 50% of its initial value and pulmonary capillary wedge pressure had risen to 20 mmHg or greater it was presumed that severe MR had been created. At this time the forcep was removed and replaced with a pigtail catheter, which was used to perform left ventricular cineangiography to confirm the severity of MR. The catheters were withdrawn, the wounds closed, and the animals recovered under veterinarian supervision. At all times, standards for animal care met or exceeded those of the American Physiological Society. Creation of AS. Puppies weighing 5-8 kg were banded at 10 wk of age (26). Briefly, after anesthesia was induced with an intravenous injection of droperidol-fentanyl, endotracheal intubation was performed, and the animals were connected to a mechanical respirator. Anesthesia was then provided by the inhalation of isoflurane. A left thoracotomy was performed, and the pericardium was incised. A cutdown was performed on the left femoral artery, and a 6-Fr sheath was inserted into this vessel. The sheath was connected to a previously calibrated fluid-filled transducer. A 5-Fr catheter was attached to a second previously calibrated fluid-filled manometer, passed through the sheath, and with the use of pressure monitoring, the catheter was advanced to the left ventricle. A 5-mm wide mersiline band was then placed around the ascending aorta 2 cm above the coronary arteries. It was tightened and held in place by a right angle clamp until an approximate 20-mm gradient existed between the femoral artery and left ventricle. The ends of the band
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HYPERTROPHY
IN
VOLUME
were then sutured together, the gradient was reconfirmed, and the right angle clamp was removed. The thoracotomy was repaired, and the animals were allowed to recover under veterinarian supervision. As growth occurred, increased cardiac output through the fixed banded stenosis increased the left ventricular pressure and transband gradient serving as a stimulus to pressure overload hypertrophy. Assessment of left ventricular mechanics 3 mo after creation of hemodynamic lesions. Three months after either MR or AS was created, the animals were brought to the experimental cardiac catheterization laboratory while under light anesthesia provided by intravenously administered droperidol-fentanyl. The animals breathed spontaneously. After the right neck was infiltrated with lidocaine for local anesthesia, a small incision was made. The right carotid artery was isolated, and a 5-Fr pigtail catheter was inserted. This catheter was connected to a previously calibrated fluid-filled manometer. Into this same vessel a double-transducer, high-fidelity, micromanometer-tipped catheter was also inserted into the left ventricle. Recordings from both micromanometers were then matched to the fluid-filled pressure tracing. The micromanometer catheter was then pulled back so that one transducer remained in the left ventricle while the other resided in the aorta. In the aortic-banded animals, the proximal transducer was always located proximal to the band. Two-dimensional short- and long-axis echocardiograms of the left ventricle were obtained from the left parasternal and apical positions. These recordings were made simultaneously with pressure recordings from the high-fidelity left ventricular catheter. Data were acquired from six healthy controls in an identical fashion to that used for the animals with MR and AS. Data acquired and calculations made. Left ventricular mass (g), body weight (kg), and the ratio of left ventricular mass to body weight were obtained for each animal. Left ventricular mass was calculated from echocardiographic measurements using the formula (34): LV mass = muscle cross-sectional area (CSA) x long axis dimension, where CSA = r(D/2 + h)2 r(D/2)“, D is left ventricular minor axis, and h is wall thickness. We have previously demonstrated an excellent correlation between echocardiographically calculated mass using the technique and actual weighed left ventricular mass made at autopsy (24, 34, 38). Left ventricular volumes (v) were calculated from the echocardiograms using the formula V =-
TD 2L 6
where L is left ventricular long-axis dimension. Left ventricular circumferential wall stress was calculated using the simultaneously recorded pressure, volume, dimension, and wall thickness data. The formula used to calculate stress was (28) (P L . D) h(2L + 0.8D + 1.6h) ’ 1*33*g-1*cm-”
VS. PRESSURE
H1139
OVERLOAD
was defined as the largest left ventricular volume during the cardiac cycle. E&l systole was defined from pressure data as the point in time where the dicrotic notch occurred and from the synchronized echocardiographic data corresponding to this point. Although the precise definition of end systole may be difficult in MR (4), these points were chosen because of their exact definition and correlation with time-varying elastance, a more precise way of defining end systole (27,33). Mean systolic stress was calculated as time-varying stress averaged over the time from the beginning of the left ventricular upstroke to the dicrotic notch as shown in Fig. 2. Assessment of hemodynamic lesions 3 mo after lesion creation. The severity of AS was assessed as the peak systolic gradient between the left ventricle and ascending aorta distal to the band. To assess the severity of MR, a slightly deeper plane of anesthesia was provided by injection of intravenous droperidolfentanyl after the echocardiographic data had been obtained. A thermodilution Swan-Ganz catheter was advanced from the right jugular vein to the pulmonary artery for the purpose of measuring forward cardiac output. Contrast tine left ventriculography was performed in the right anterior oblique position. Cineangiographic left ventricular stroke volume (total stroke volume) and forward stroke volume (thermodilution cardiac output/heart rate) were used to calculate regurgitant fraction using the formula: regurgitant fraction = total stroke volume forward stroke volume/total stroke volume. This method has been previously validated in our laboratory (6,27). Left ventricular function was assessed using the relationship between mean velocity of circumferential fiber shortening ( VCF) and end-systolic wall stress (6, 8, 12). This relationship assesses contractile function by correcting an afterload-sensitive ejection phase inand its 95% confidence dex, VW, for afterload. The relationship limits were developed from eight normal subjects against which the animals with hypertrophy were then plotted. The VCF was calculated as V CF=
EDD - ESD EDD ET l
where EDD is end-diastolic dimension, ESD is end-systolic dimension, and ET is ejection time. ET was determined from the beginning of minor axis shortening on the echocardiogram to the dicrotic notch of the aortic pressure tracing. This definition of ET was used to account for the fact that in MR substantial ejection occurs before aortic valve opening but little occurs after aortic valve closure (15). Statistics. When the five groups of subjects were compared, analysis of variance was used to detect differences among the groups. If a difference was found to exist, a Newman-Keuls test
l
where P is left ventricular pressure. Left ventricular pressures were digitized, and pressure data were retrieved at 5-ms intervals. These data were then synchronized in time to the appropriate echocardiographic data. The frame rate for our two-dimensional echocardiograms was 30 frames/s. Pressure-volume and stress-volume loops were then developed from these data. Stroke work (SW) is the area within the pressure-volume loop (Fig. 1A). Mathematically it is described as SW = J Pdv. The integral was obtained from the digitized pressure volume data with the aid of a computer. We then multiplied this integral by 0.0136 to convert from millimeters of Hg for expression in the standard units, gram. meters. Stroke work normalized for the myocardium present was calculated as the area within the stress-volume loop as shown in Fig. 1B. End-diastolic volume
;200 E 0 -ml50 -
z
w100 E cn
50
0 60
TIME Fig. 2. Time-varying systolic stress from gitation is demonstrated. Stress averaged systolic stress (118 g/cm”).
(ms) an animal over time
with mitral regurof systole is mean
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H1140
HYPERTROPHY
IN VOLUME
was performed to find where the differences were located. Regression analysis using the least squares technique was used to develop the VcF- stress relationship. Dispersion from the mean is noted as means t SE. RESULTS
Severity of disease. The animals with volume overload had severe MR with an average regurgitant fraction of 0.62 t 0.02. Th e 1eft ventricular peak systolic pressure in the ASH, group was 160 t 12 mmHg. This was significantly less (P < 0.05) than the peak left ventricular systolic pressures in the ASsw group (212 t 16 mmHg) or the ASDys g roup (220 t 25 mmHg). Left uentricular hypertrophy. Left ventricular mass was evaluated in relationship to body weight and is described as the ratio of left ventricular weight (g) to body weight (kg) (LVBW). As shown in Fig. 3, the LVBW was significantly elevated compared with normals in all the experimental groups. The LVBW was similar in the MR and the ASH, groups by design. This ratio was significantly higher in the AS sw group than either the MR or the ASH, groups (P < 0.05). The LVBW was significantly higher (P < 0.05) in the ASpYs group than all other groups. The ratio of mass to volume was depressed in the MR group (1.13 t 0.05) compared with normal (1.65 t 0.15; 11
n
10
:i
9 A
VS. PRESSURE
P < O.Ol), with ASH, (2.03 t 0.06; P < O.Ol), with ASsw (2.46 + 0.20; P c O.OOl), and with ASpys (1.84 t 0.35; P = 0.02). The ratio was increased in the ASsw compared with normal (P < 0.05). Stroke work. Stroke work for the five groups is shown in Fig. 4. Stroke work was significantly elevated compared with normal in the MR and ASsw groups (P < 0.01). By design the MR and ASsw groups were matched to be equal. Pressure volume loops (the area enclosed by which is stroke work) are demonstrated for the matched pairs of MR and AS sw dogs in Fig. 5. While the areas are matched to be equal, the shapes are quite different. Comparison of stroke work between the MR and ASH, groups, which were matched for hypertrophy, shows that the stroke work associated with this amount of hypertrophy was less in the ASH, group than the MR group (P < 0.05). Thus similar amounts of hypertrophy in the ASH, and MR groups were associated with less stroke work in the ASH, group than the MR group. Normdized stroke work. Normalized stroke work (the area within the stress-volume loop) is demonstrated for the five groups in Fig. 6. Normalized stroke work was not different among normals and in the ASsw and ASH, groups, although it tended to be higher in ASsw group. Normalized stroke work was significantly elevated (P C 0.01) in the MR group and in the ASDys group, the two groups with decompensated left ventricular function. Left ventricular function. Figure 7 demonstrates the relationship of the mean velocity of circumferential fiber shortening ( VCF) and end-systolic stress in the five groups of animals. Five of the six animals with MR and all of the A& animals fell down and to the left of the normal relationship, indicating reduced velocity of shortening for any given afterload, which suggested impairment of contractile function. WalZ stress. Figure 8 demonstrates end-diastolic and mean systolic wall stress for the experimental groups. End-diastolic stress was elevated in the MR, A&w, and AS pYs groups. Mean systolic stress was elevated only in the AS Dys group*
100
4
OVERLOAD
-
80 -
R (D
8
3 NL
MR *
AShy *
*%v * t+
*‘dys * t+s
Fig. 3. Ratio of left ventricular weight (LV) to body weight (in g/kg) is demonstrated for normal subjects (NL), subjects with mitral regurgitation (MR), subjects matched to have similar aortic stenosis hypertrophy to MR group (AS,,), AS subjects matched to MR group to have similar stroke work (AS,,), and subjects with AS and left ventricular dysfunction (AS,,,). Statistics are demonstrated beneath group labels. * P < 0.05 vs. control, t P < 0.05 vs. MR, $ P c 0.05 vs. ASHy, and Q P c 0.05 vs. AS SW. Ratio was increased in all experimental groups indicating presence of left ventricular hypertrophy. However, when MR and AS groups were matched for stroke work, ASsw had significantly more hypertrophy than MR group. The most hypertrophy was seen in ASyS grow.
20 -
0 NL
MR
AS
*
t
hY
ASsw *+
ASdys
Fig. 4. Stroke work is demonstrated for all five groups. Abbreviations and statistical analysis are same as in previous figure. ASH, group, which was matched to have same amount of hypertrophy as MR group, produced significantly less stroke work than did MR group.
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HYPERTROPHY
N VOLUME
VS. PRESSURE
H1141
OVERLOAD
cl 1
0
a a I 3 0
a -
300
40
120
160
300
cl4
300
cl5
cl6 .
9.
l
200
‘9 . .’
F z
200
.
9 ’
200
.
b b . l 63
‘9 a .
. . . a
100 a 0 a 0 . .
t
W A
.*
. .
.
:
100
’ .
0
. . . . .
W >
00
86
. ..-•
o-
Ts.
0
)
40
80
120
160
0 0
40
80
LEFT VENTRICULAR Fig. 5. Pressure-volume loops are demonstrated loops (stroke work) were matched to be nearly
for MR identical,
120
160
0
VOLUME
A*,
T
nt
160
by
-O-
\*.
8
120
(ml)
group and for AS sw groups. Although areas surrounded the difference in shape of loops is quite obvious. 2.5
0
80
40
**
CONTROL X
MITRAL
REGURGITATION
0
AORTIC
STENOSIS
(HY)
A
AORTIC
STENOSIS
(SW)
STENOSIS
(DYS)
X
1
OJ
NL
MR *
AShy
t
ASsw
t
*xsdys
Fig. 6. Normalized stroke work (area surrounded by stress-volume loop) is shown for five groups. Abbreviations and statistical analysis are same as shown for previous figures. In two groups with dysfunction (MR, AS&, normalized stroke work was significantly greater than normal. In other two compensated AS groups, normalized stroke work was not greater than normal and was less than MR groups. DISCUSSION
Comparison of pressure overload hypertrophy to volume overload hypertrophy is made difficult by the differences in the hemodynamic variables between the two types of overload. The current study helps to circumvent this problem by matching the lesions at various points of commonality. This study demonstrated that the hypertrophic response to the volume overload of MR was less than the hypertrophic response to pressure overload. This conclusion is based on three findings. First, when matched by stroke work, the chronic volume overload of experimental MR produced less left ventricular hypertro-
1 60
80
END
1
I
1
1
I
I
100
120
140
160
180
200
SYSTOLIC
STRESS
(gm/cm2)
Fig. 7. Relationship of mean velocity of circumferential fiber shortening (I&) vs. end-systolic stress and confidence limits for normal subjects is demonstrated. Five of the six MR dogs and all of the ASnys dogs fell down and the left of this relationship indicating impaired contractile function.
phy than did equal stroke work produced by the chronic pressure overload of experimental AS. Second, when MR and AS dogs were matched for the amount of hypertrophy present, the stroke work associated with this amount of hypertrophy was greater in the MR group than the ASH, group, suggesting that more overload in volume versus pressure overload was required to produce the same amount of hypertrophy. Finally, in both the decompensated groups (MR and AS,,,), normalized stroke work was elevated, indicating that each unit of myocardium had to perform more work than normals or the compensated AS groups. Thus in both cases the hvpertrophv was
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Hl142
HYPERTROPHY 100 90 80
IN VOLUME
1 A
1 X
NE 60 x50
0 0 %
0j
- B : : : : : : : -
n n
iid
n
T
i
A
A
0
Cl MR *
NL
320 300 280 260 240 220 200 "E 180 -9 160 ;140: v,120=1001 80 60 40 20
A
AS
AS
ASsw *
hY
* dYS
A X
m 4
: : : : 0' NL
MR
AShy
ASsw
ASdys
*t9 Fig. 8. A: end-diastolic stress (EDS) is demonstrated for the five groups. B: mean systolic stress (MSS) is demonstrated for the five groups. Mean systolic stress was elevated only in the ASijys group. Abbreviations and statistical analysis are same as shown for previous figures.
inadequate to norma lize stroke work per unit of myocardium. Howeve lr, this normalization failed to occur in MR becau se only a modest amount of hypertrophy had d.evelOPd whereas in AS the hypertrophy was extreme. This dichotomy suggests two different explanations for the inadequate hypertrophic response, when it occurred, in the two diseases. In MR the relatively small amount of hypertrophy present suggests that the hypertrophic response failed to be induced. In the A& group, the extreme hypertrophy present suggests that some biological limit of hypertrophy might have been reached beyond which hypertrophic compensation was impossible (19). In the ASDys dogs and in five of the six MR dogs these changes were also associated with a deficit in contractile function, which did not occur in nine of the 10 other AS animals. Whether the increased normalized stroke work in MR and the ASDys dogs and the contractile deficit are causally related cannot be stated definitively from our results. We postulate however that there may be cause and effect, since hemodynamic overload is generally considered responsible for muscle dysfunction in overload states (3, 10, 20, 32). While previous studies of pressure overload have shown that severe left ventricular hypertrophy as is present in our A& group is associated with left ventricular dysfunction (16, 23), the current study further suggests that inadequate hypertrophy in volume
VS. PRESSURE
OVERLOAD
overload also may occur and lead to ventricular dysfunction but at much less severe degree of hypertrophy. Consistent with our finding of increased normalized stroke work in MR is the finding that the mass-to-volume ratio was depressed in this model. Thus there was less mass present relative to the volume being pumped. In all of our previous investigations of experimental MR, the mass-to-volume ratio and/or the of wall thickness-toradius (which is concordant with mass and volume changes) was also depressed in animals with decompensated left ventricular function (6,25,27). Our finding of a reduced mass-to-volume ratio in experimental MR is in agreement with reports concerning this lesion in humans. Corin et al. (11) in an angiographic study of humans found mass index to volume index was 1.03 in normal subjects but was reduced to 0.70 in patients with MR. Schuler et al. (31) used echocardiography to study left ventricular mass and geometry in patients with MR. Reanalysis of their data revealed an estimated mass-tovolume ratio of 1.52 in patients with compensated MR but only 0.91 in those patients with decompensated MR. Likewise, Wong and Spotnitz (37) found a mass-tovolume ratio of 1.52 in patients with coronary disease and normal left ventricles; this ratio was depressed to 1.19 in patients with MR. If the hypertrophy that developed in the MR group is truly inadequate, the question remains why fully compensatory hypertrophy failed to occur. Unlike the severe hypertrophy in the A& group where a biological limit to the hypertrophy could have been met, the hypertrophy in the MR groups was relatively mild. Why more hypertrophy did not develop is unclear. The stimulus for hypertrophy is proposed to be systolic and diastolic wall stress (18). Acute MR leads to a depression in systolic wall stress (27), which could theoretically cause a reduction in muscle mass, since the stimulus for maintaining muscle mass is reduced. With time, chamber dilatation increases the radius term in the stress equation thereby increasing systolic wall stress to normal as it was in this study. However, only when ejection performance is severely depressed in MR does systolic wall stress become higher than normal (11) where it might serve as a stimulus to hypertrophy. While diastolic stress was elevated in the animals with MR, previous investigations have suggested that diastolic stress is a less effective stimulus to hypertrophy than systolic stress (18, 21, 29). Thus it may be that increased diastolic stress in the face of normal systolic stress leads to only mild hypertrophy in MR. This differs from aortic regurgitation where both systolic and diastolic wall stress are increased (36) and the hypertrophic response is generous. In support of this concept, reanalysis of Grossman’s et al. (18) original data regarding hypertrophy in humans found the ratio of thickness to radius in MR to be 0.29 t 0.02, which was significantly less than that seen in aortic regurgitation (0.38 t 0.03). The above discussion focuses on differences in load between MR and aortic banding as the key determinants of the hypertrophic response and its adequacy. However, differences in neurohumoral mechanisms between the two models may also have been operative and could help
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HYPERTROPHY
IN VOLUME
explain differences in modulation of the hypertrophic response (9). Our study was not designed to assess these influences. Regardless of the mechanism involved, the result was that there was relatively less ventricular muscle mass to meet stroke work demands in animals with MR compared with normals or animals with AS. MR is probably exceptional in leading to this sort of hypertrophic response, since it is the only common low pressure (“pure”) volume overload where the excess volume pumped is ejected into the relatively low pressure of the left atrium (6). In other types of left ventricular volume overload such as anemia, aortic regurgitation, heart block, etc., the excess volume is ejected into the higher pressure of the aorta. Limitations. It should be noted that pressure overload hypertrophy was induced in young dogs, whereas volume overload hypertrophy was induced in adults. Quantitative and qualitative differences between the young heart, which is developing both physiological (growth) hypertrophy and pathological hypertrophy, and the adult heart experiencing only pathological hypertrophy could exist. Our study cannot directly address this question. However, adult dogs experiencing pressure overload from valve plication performed in adulthood can develop a similar amount of hypertrophy to our younger group (1). Thus the magnitude of hypertrophy seen in our younger pressure overload group cannot be explained simply by the young age, since pressure overloaded adults can also develop a similar amount of hypertrophy. Thus the difference in the type of load between MR and AS rather than the difference in age is the likely explanation for our results. Furthermore, Bathe et al. (2) found no differences with respect to coronary blood flow in adult versus juvenile animals with pressure overload hypertrophy, suggesting that at least this feature of hypertrophy is not different between adults and juveniles. Another concern regarding the variation in age among our groups is whether the ratio of left ventricular weight to body weight varies with age. If it did, our adult control group might not be a fair standard against which to judge the younger animals. However, this ratio has been reported to be 3.9 t 0.14 in 7- to 8-mo-old dogs similar in age (6 mo) to the dogs reported here and nearly identical to the value for the current adult controls (5). Thus left ventricular weight/body weight seems a fair reference for comparison of the amount of hypertrophy between the groups. A second potential cause for the discrepancy in the hypertrophy between the two models is the acuteness of the overload in the MR group versus the more chronically imposed overload in the AS group. We can only speculate about what difference this might cause. However, we believe the models employed remain relevant in this regard, since many pathological volume overloads (valvular endocarditis, chordal rupture, papillary muscle dysfunction) occur acutely compared with most pressure overloads, which develop more chronically. Contractile function in this study was assessed using the mean VcF-stress relationship (6, 8, 12). The imprecision in defining end systole in MR could lead to inaccuracy of this method in that group of dogs. However, our
VS. PRESSURE
H1143
OVERLOAD
conclusion that contractile function was depressed in MR using this technique is identical to our assessment of contractile function in MR in previous studies using more accurate and sophisticated techniques (6, 7,27). Thus we probably judged contractile function accurately when we found it was depressed in MR and ASDys animals in this study. Finally, we acknowledge that retrospective analysis is always fraught with potential bias. However, we believe that random selection of the MR dogs followed by consecutive matching with the AS dogs helped to mitigate methodological bias. In conclusion, volume overload induced by MR produced strikingly less left ventricular hypertrophy than did a stroke work-matched pressure overload. In MR the hypertrophy was inadequate to normalize stroke work per unit of myocardium, a feature in turn associated with contractile dysfunction. Inadequate hypertrophy also occurred in some subjects with pressure overload. However, while the hypertrophy in these pressure overload subjects was inadequate to normalize stroke work per unit of myocardium, the amount of hypertrophy was extreme, unlike in MR where it was mild. These data suggest that in MR, inadequacy of hypertrophy results from failure of the hypertrophy to be induced while in pressure overload, inadequacy may result when some biological limit to hypertrophy is met. This research was supported in part by the Research Service of the Dept. of Veterans Affairs, Washington, D.C. (to M. R. Zile, G. Cooper IV, and B. A. Carabello) and by a National Heart, Lung, Blood Institute Grant ROl-HL-38185 (to B. A. Carabello). Address for reprint requests: B. A. Carabello, Cardiology Division, Medical Univ. of South Carolina, 171 Ashley Ave., Charleston, SC 294252221. Received
30 October
1991; accepted
in final
form
2 June
1992.
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HYPERTROPHY
IN VOLUME
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VS. PRESSURE
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