Download Pathogenesis of ventricular hypertrophy

JACC Vol. 5. No.6
June 1985:578-658
578
MORPHOLOGIC SUBSTRATES OF SUDDEN DEATH
Thomas N. James, MD, FACC, Moderator
Pathogenesis of Ventricular Hypertrophy
SUZANNE OPARIL, MD
Birmingham, Alabama
Growth of the vertebrate heart during embryonic and
fetal life is characterized by hyperplasia of myocardial
cells. Shortly after birth, myocardial cells lose the capability of dividing, and further growth of the heart is
due to myocardial cell hypertrophy and nonmuscle cell
hyperplasia. This process results in a 30- to 4O-fold increase in volume of individual myocardial cells during
normal postnatal growth and maturation. The transition
from hyperplastic to hypertrophic growth is related to
formation of binucleated myocardial cells as a result of
karyokinesis without cytokinesis. The molecular mechanism of this transition is uncertain.
The response of the heart to increased metabolic demands or an increased work load depends on the age of
the animal at the time when the stress is imposed. Increased myocardial work loads in fetal or early neonatal life lead to cardiac enlargement by causing an increased rate of hyperplasia of myocardial cells or
continuation of hyperplasia beyond the normal period
Normal Cardiac Growth
The cellular mechanism of hypertrophy is determined by
the age of the subject at the time that the stimulus to hypertrophy is introduced and the pattern of normal myocardial
growth at that age. During fetal and early neonatal life, the
hyperplastic phase (birth to 4 days postpartum) of myocardial growth, the heart enlarges by increasing the number
of mononucleated myocardial cells (1-5). Estimates of myocardial cell numbers in neonatal and adult hearts of various
species based on morphologic techniques have shown that
the number of myocardial cells present in the adult is substantially greater than that found at birth, supporting the
From the Cardiovascular Research and Training Center, University of
Alabama in Birmingham, Birmingham, Alabama.
Address for reprints: Suzanne Oparil, MD, Cardiovascular Research
and Training Center, 1012 Zeigler Building, University Station, Birmingham, Alabama 35294.
© 1985 by the American College of Cardiology
of hyperplastic growth. In contrast, imposition of increased loads on the hearts of older animals results in
cardiac hypertrophy due to enlargement of myocardial
cells and hyperplasia of nonmuscular components. In
addition to cellular enlargement, structural remodeling
of the myocardial cells and of the chambers of the heart
occurs during the development of hypertrophy.
Important stimuli of cardiac hypertrophy include increased systolic force or tension generated by the myocardial fibers (pressure overload), increased end-diastolic wall stress (volume overload) and neurohumoral
factors such as increased circulating catecholamines or
discharge of cardiac sympathetic nerves, or both, activation ofthe renin·angiotensin system and increased levels of thyroxine and growth hormone. Myocardial growth
factors may provide a biochemical basis for genetically
based myocardial hypertrophy.
(J Am Coli CardioI1985;5:57B-65B)
notion that myocardial cells undergo hyperplasia during growth
(6). There is an approximately twofold increase in total
myocardial cell number from birth to age 21 days. In contrast, normal heart growth from age 21 days to adulthood
appears to be due to hypertrophy of myocardial cells.
Mononucleated versus multinucleated myocardial
cells. At birth almost all myocardial cells are mononucleated, but adult hearts have multinucleated myocardial
cells. Adult members of most mammalian species have predominantly binucleated myocardial cells (7). In human beings,
18 to 25% of myocardial cells are binucleated, but there is
a high incidence of polyploidy (Table 1). Furthermore, the
incidence of polyploidy in human myocardial cells increases
with advancing age and the development of hypertrophy (8).
Several mechanisms by which mononucleated myocardial cells could become binucleated have been proposed:
I) fusion of mononucleated cells (9), 2) amitotic nuclear
division (10), and 3) mitotic division of nuclei without cy0735-1097/85/$3.30
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PATHOGENESIS OF VENTRICULAR HYPERTROPHY
58B
JACe Vol. 5, No.6
June 1985:57B-65B
Table 1. Ploidy Frequencies of Left Ventricular Myocytes of Various Mammalian Species
Species
2c
4c
8c
."
Rat
6'/2 weeks
17 to 18 weeks
Dog
~
4
2
93 to98
2 to7
82
14
4
88
29
8 to 14
55
16
45
20
o to 10
47
50
10 to40
8
35
45 to65
Cattle
Pig, adult
Monkey, Rhesus
3 to4 years
8 to 10 years
Human heart weight
150 g
250 to500 g
500 to750 g
32c
v
96
98
'Cat' bit} adult
16c
\.
...
2.8
5
15 to30
o to5
(Reproduced from zak R. Development and proliferative capacity ofcardiac muscle cells. Circ Res 1974;
34/35 [suppl 11]:11-21 , with permission ofthe American Heart Association, Inc.)
toplasmic separation (karyokinesis without cytokinesis)
u.r.m.
Fusion of myocardial cells. The proposal of fusion of
myocardial cells is based on observationsfrom skeletal muscle systems (Fig. 1). Skeletal muscle cells originate from
presumptive myoblasts, a group of spindle-shaped mononucleated cells with prominent mitotic activity but no specific muscle proteins. Myoblasts then fuse with one another
to form a multinucleated fiber, known as a myotube, which
Figure 1. Scheme of muscle cell differentiation in skeletal and
cardiac muscle. (Reproduced from ZakR; Development and proliferative capacity ofcardiac muscle cells. Circ Res 1974;34/35[suppl
11]:11-19, with permission oftheAmerican Heart Association, Inc.)
SKELETAL MUSCLE
I
0- PROLIFERATE!
'"
,--/\
-J! i
(~
MITOSIS (1)
SPLANCHNIC MESODERM
I MYOCARDIAL
~~
aUANTAl
HEART
I
lA TERAl PLATE MESODERM
I
R~N
,"OCACfi '£.'0'
t
~RJ
MYOBlASTS
I
1
'1;J
CONNECTIVE
Q2)~ TISSUE
\
~~~--~ IMvCECAi'!S -riJf'~.~
, .. )
CEllS
FUSION
I
~~:'~~lMY01UlE!
.......... J !
\ SATElliTE CElli
~I
i;\illli.',fl.l ,'} Myo·1
.s
-
--
FIBER
I
I
@)<!D@>~
~
+
~J
MYOCYTES
matures into the myofiber. The mature myofiber contains
within its basement membrane a group of undifferentiated
cells known as "satellite cells" that have myogenic properties and serve as a source of nuclei in postnatal growth
(12). Satellite cells are capable of giving rise to myoblasts
or additional satellite cells. Myocardial cells also have the
potentialto fuse in vitro, forming multinucleated myocardial
cells (10,13) . Thus, cell fusion must be considered as a
possible mechanism for formation of multinucleated myocardial cells.
Amitotic nuclear division. This has been adduced to explain the increase in number of myocardial cell nuclei in
adults compared with neonates. Evidence for this mechanism is indirect and is based on morphologic obsetvations
of the appearanceof nuciei in the hearts of growing animals
(7). Polyploid nuclei must be produced for amitotic nuclear
splitting to occur (14). Because polyploid nuclei have not
been observed in the rat heart in the early neonatal period,
it is unlikely that binucleated myocardial cells in neonatal
rats form as a result of amitotic splitting of polyploid nuclei.
DNA synthesis. Differentiated myocardial cells can
synthesize DNA and undergo mitosis (15,16). Thus, continued mitotic division of a riucleus without cytoplasmic
separation (karybkinesis without cytokinesis) may be responsible for the formation of multinucleated myocardial
cells. Supportfor this mechanismis basedon the observation
of active myocardial cell DNA synthesis and mitosis in the
early neonatal period (17) . During the transitionperiod from
mono- to binucleatedcells in the rat heart (age 6 to 14 days),
mitotic figures occur in differentiated myocardial cells (3).
The percent of myocardial cells observed in mitosis is approximately 2% at birth, decreasing to less than 0 .1% by
age 4 weeks (Fig. 2) (14).
Role of age. DNA synthesis is active in rats at birth,
then decreases progressively and essentially stops by age 3
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
JACC Vol. 5. No.6
June 1985:57B-65B
PERCENT MITOSES
IN
~I- a::
~~ w
ow >
Figure 2. Mitotic activity of various cell types at
different stages of rat growth: I = hepatocytes,
2 = heartconnective tissuecells, 3 = heartmyocytes
and 4 = skeletal muscle (tongue). (Reproduced with
permission from Zak R. Development and proliferative capacity of cardiac muscle cells. Circ Res
1974;34/35 [suppl II]:II-18, with permission of the
American Heart Association, Inc.)
I- J:
...J
598
~24
\
\
\
1!5
\
3
10
-2 -1
0
I
2
3
4
!5
6
7
8
9
WEEKS
weeks (18). Enzymes essential for DNA replication have
been shown to be lost from isolated rat myocardial cells by
age 3 weeks (19). Progressive decreases in alpha-DNA polymerase and chromatin transcriptase activities have been described with advancing age, while beta- and gamma-DNA
polymerase remain unchanged (20) . The time course of
decrease in activity of enzymes necessary for DNA replication is parallel with the restriction in proliferative capacity
of cardiac myocytes (20) . One explanation of these findings
is that there is a decrease in DNA accessibility for gene
transcription, resulting in loss of mitotic potential by myocardial cells. Bugaisky and Zak '(21) postulated that a chalone-like molecule accumulates in the myocardial cell during growth. Once this molecule reaches a critical concentration, DNA synthesis shuts off. If, however, the heart is
stressed before the critical chalone levels are reached, the
myocardial cell can still synthesize enzymes necessary for
stimulating DNA synthesis, thus resulting in further mitosis
and extension of the period of hyperplastic growth (21).
Enlargement of myocardial cells. Once DNA replication and mitosis in myocardial cells cease , further cardiac
growth is accomplished by enlargement of myocardial cells
and hyperplasia of nonmuscular components of the myocardium . During the hypertrophic growth phase, which begins at approximately 15 days postpartum in the rat, there
is stabilization in the percent of binucleated cells, negligible
myocardial cell DNA activity and no significant increase in
myocardial cell numbers . Nevertheless, the heart continues
to increase in weight, and there is a significant increase in
myocardial cell length from age 15 to 28 days with a concomitant increase in myocardial cell volume. The volume
of individual myocardial cells increases 30- to 40-fold during normal postnatal growth and maturation in the period
after cessation of hyperplastic growth .
MONTH
Effects of Stress on Neonatal Cardiac Growth
The mechanism by which the neonatal heart responds to
stress is fundamentally different from that of the adult heart.
In the transitional growth phase or early in the hypertrophic
growth phase, the neonatal rat myocardial cell can reinitiate
DNA synthesis when stressed even though mitotic index,
alpha-DNA polymerase and thymidine kinase levels are similar to those measured in normal adult hearts (3,7,17) . Renewed DNA synthesis has been interpreted as indicative of
myocardial cell hyperplasia (2,7,17). Alternatively, increased myocardial cell DNA could reflect cell hypertrophy
with increased numbers of bi-, tri- and tetranucleated cells.
The increased DNA observed in stressed neonatal hearts has
not been observed in adult rat hearts and, therefore, represents a form of cardiomegaly that is unique to the neonate .
Effects of Stress on Cardiac
Growth in Adults
Increased myocardial work load in adult animals leads
to enlargement of myocardial cells and to hyperplasia of
nonmuscular components of the myocardium. There is no
mitotic activity in myocardial cells, but increased DNA
synthesis does occur in nonmuscular components of the
myocardium (5).
Work load and myocardial cell size. Numerous studies
have demonstrated that in the presence of augmented work
load on the heart with associated increases in heart weight ,
there is a detectable increase in the cross-sectional area or
diameter of myocardial cells (22) . Recent reports (23) have
also shown increases in myocardial cell length in the hypertrophied heart. Relative changes in length and width of
myocardial cells may be related to the nature of the work
608
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
overload placed on the heart. Myocardial cells appear to
undergo a relatively greater increase in length than in width
in hearts subjected to a volume overload and cardiac dilation, while a greater increase in width occurs in hypertrophy
due to a pressure overload unaccompanied by chamber dilation (22).
Biochemical changes. Increased RNA polymerase activity is one of the earliest biochemical changes observed
in developing cardiac hypertrophy in adult animals, occurring within 12 to 24 hours after aortic constriction in the
rat (24). This enzyme is responsible for RNA synthesis,
which in tum produces ribosomes, transfer RNA and messenger RNA. Increased RNA concentration per gram of
heart tissue and increased total cardiac RNA content, reflecting an increased number of ribosomes, have been observed in cardiac hypertrophy induced by a variety of experimental procedures (24). When the sustained phase of
cardiac hypertrophy is reached, total RNA content decreases
below the peak levels observed in developing hypertrophy
but still remains above control levels (25). Heart weight and
total protein content are higher than those of control animals.
Mitochondrial versus cell volume ratios. Within 48
hours after aortic banding, mitochondrial mass increases.
The increment in mitochondrial mass occurs more rapidly
than the increase in myofibrillar components of the cell, so
there is an increased mitochondria to cell volume ratio early
in the course of developing hypertrophy (26). When the
heart reaches a state of stable compensated hypertrophy, the
mitochondria to myofibril ratio normalizes (27). If myocardial failure develops, a decreased mitochondrial to cell
volume ratio and an increased number of small (immature)
mitochondria are found, suggesting that the cell attempts to
compensate for the adenosine triphosphate (ATP) deficiency
by rapidly producing immature forms of mitochondria (22).
Myofibrillar changes. Morphologic changes in myofibrils appear as hypertrophy develops. The most striking of
these is expansion of Z-band material. The intercalated disc
in hypertrophied myocardial cells has an increased surface
area and enhanced folding of its transverse segments (22).
Multiple intercalated discs that have been described as transverse disc areas separated by 1 to 10 sarcomeres within a
single cell have been found in hypertrophied human and
animal hearts. These are a morphologic expression of increased intercalated disc area in the hypertrophied myocardial cell and are thought to beinvolved in sarcomerogenesis.
In summary, imposition of increased loads on the hearts
of adult animals results in cardiac hypertrophy due to enlargement of myocytes and hyperplasia of nonmuscular
components of the myocardium. In addition to cellular enlargement, structural remodeling of the myocyte, including
alterations in relative proportions of cellular organelles and
in the ultrastructure of individual organelles, occurs during
the development of hypertrophy in the adult heart. The
precise nature of the cellular remodeling process is dependent on the stimulus to hypertrophy.
JACC Vol. 5. No.6
June 1985:57B-65B
Pathogenesis of Ventricular Hypertrophy
Mechanical Factors
Heart size and left ventricular wall tension and pressure. Cardiac muscle normally grows to compensate for
the work load imposed on the ventricle. Classically, the
most important factor mediating cardiac hypertrophy has
been thought to be the systolic force or tension generated
by the myocardial fibers (28). The relations among left
ventricular wall tension, intracavitary pressure and heart size
can be expressed by the law of Laplace. Assuming that the
ventricle is a thin-walled sphere, wall tension (T w) is proportional to pressure (P) and the radius of curvature (r) (29):
T; = Pr/2. For spheres with a significant wall thickness
(WT) , this becomes T; = Pr/2WT or P = T; x 2WT/r
(30). When a chronically increased pressure load is imposed
on the ventricle, left ventricular wall thickness increases so
that the left ventricular peak systolic wall stress remains
unchanged and within normal limits (31-33). Thus, P (pressure) = a constant (K) x WT/r, so that the ratio of WT/r,
or relative wall thickness of the left ventricle, is directly
proportional to the intracavitary pressure, and in cases in
which left ventricular outflow tract obstruction is absent, to
the systolic blood pressure (30).
Pressure-overloaded left ventricles tend to develop concentric hypertrophy and an increased ratio of wall thickness
to radius of the left ventricular cavity (Fig. 3) (28). These
changes occur whether the increased pressure load is due
to aortic stenosis, systemic hypertension or some other lesion. In contrast, volume-overloaded left ventricles develop
eccentric hypertrophy and proportionate increases in left
ventricular radius and wall thickness so that relative wall
thickness remains within the normal range. In this situation
if systolic pressure remains unchanged, wall thickness and
the radius of the curvature increase proportionally, causing
a "magnification" of the left ventricle.
There are exceptions to these general rules governing
patterns of left ventricular hypertrophy. For example, Savage et al. (34) reported ventricular septal thickening that
was disproportionate to the left ventricular free wall thickness in a small proportion (4%) of hypertensive patients.
The demonstration of asymmetric septal hypertrophy in hypertensive hearts raises the question of whether this cardiac
abnormality is etiologically related to the hypertension or
whether it represents an independent genetically mediated
event. Further study is needed to resolve this issue.
Alterations and pattern of ventricular hypertrophy.
To examine the role of alterations in systolic and diastolic
wall stresses in influencing the pattern and extent of left
ventricular hypertrophy in human beings, Grossman et al.
(33) examined systolic and diastolic wall stresses in a series
of patients with a normal or chronically pressure-overloaded
or chronically volume-overloaded left ventricle (Fig. 3).
Left ventricular systolic pressure was increased only in the
pressure-overloaded group, while left ventricular diastolic
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
JACC Vol. 5. No.6
June 1985:57B-65B
0.7
~
0.6
s:
a::
*
h/R 01
END DIASTOLE
~ h/ R at PEAK
SYSTOLIC
STRESS
oc
<,
*
0.5
«
...J
:J
u
0,4
ir
~
Z
LV PRESSURE
(mmHg)
117t7/10tl
226t6'/23t3'
138t 7123t2'
LVMI
(gm/m 2 )
71t8
206 t 17'
196 t 17'
LV WALL
THICKNESS
(mm)
8.2 t .6
15.2 t .9'
.34 t.03
.56 t.05*
33t02
161 t 24
23t 3
175t7
41t3*
h/R
o
61B
UJ
0.3
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UJ
...J
IO.6t .5'
O"m (10 3 dy_/cm 21
PEAK SYSTOLIC 151 t4
17t2
END DIASTOLIC
·pc .OI
Figure 3. Left ventricular (LV) pressure, left ventricular mass
index (LVMI), left ventricular wall thickness, ratio of wall thickness to internal radius (h/R) at end-diastole and meridional left
ventricular wall stress (am) in patients with a normal heart compared with those with chronic left ventricularpressure overload or
volume overload. Only patients with chronic left ventricular pressure or volume overload who were well compensated and had no
depression of systolic function (left ventricular ejection fraction)
were included. (Reproduced with permission from Grossman W,
et al. [33].)
pressure was increased equally in both the pressure-overloaded and the volume-overloaded group. All patients were
well compensated in terms of systolic performance, and left
ventricular mass was increased to more than twice normal
in both patient groups, indicating significant hypertrophy.
Left ventricular wall thickness was significantly increased
in both groups, but was disproportionately increased in the
group with pressure overload, indicating the presence of
concentric hypertrophy. The ratio of left ventricular wall
thickness to internal radius of the left ventricle was normal
in patients with left ventricular volume overload but significantly increased in patients with pressure overload (Fig.
4). These differences were noted when measurements were
made at end-diastole as well as at the time of peak systolic
stress.
Average meridional or longitudinal stress was calculated
throughout the cardiac cycle as part of the study of Grossman et al. (33) . Figure 5 illustrates the theoretical basis for
such calculations. Left ventricular wall stress is a function
of chamber size and configuration, thickness of the ventricular wall and intracavitary pressure. Assuming that the
ventricle is either an ideal ellipsoid or a perfect sphere,
average meridional stress (am) is defined as the force per
unit area acting at the midplane to the heart in the direction
of the apex to base length (33). Meridional wall forces must
be equal to the pressure load if the ventricle is to hold
0 .1
NORMAL VOLUME PRESSURE
L- OVERLOAO.-J
Figure 4. Ratio of left ventricularwall thickness to internalradius
(h/R) at end-diastole (clear bars) and at the time of peak systolic
stress (hatched bars) . Wallthickness/internal radius ratio is normal in patients with left ventricular volume overload, but significantly increased in patients with pressure overload. Bars and
brackets represent mean values and standard errors, respectively .
(Reproduced with permission from Grossman W, et al. [33].)
together. Derivation of the equations representing this relation (Fig . 5) permits calculation of an average meridional
or longitudinal stress throughout the cardiac cycle from simultaneous echocardiographic and invasive measurements
of left ventricular pressure, wall thickness and radius (33).
Figure 6 is an example of wall stress measurements obtained
throughout the cardiac cycle in a representative normal subject. Peak systolic meridional stress usually occurred early
in ejection (40 to 60 ms after aortic valve opening); enddiastolic measurements were taken at the time of the peak
Figure 5. Diagrammatic representation of an idealized left ventricular chamber in coronal section, looking from the front (left)
and above (right). Wall thickness (h), inner radius (R) and outer
radius (Ro) are required to calculate meridional wall stress (am).
This is accomplished by equating the meridional wall forces (am
x 7T [Ro2 -R? D to the pressure (P) loading (P7TR?), since these
must be exactly equal if the ventricle is to hold together. The same
calculation applies for either an ellipsoid or a spherical model.
(Reproduced with permission from Grossman W, et at. [33].)
2-R 2)=P7TR?
a.m
7T(R
Ol
I
O"m
=PRj/2h(1 +h/2Rjl
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
62B
JACC Vol. 5, No.6
June 1985:57B-65B
group (220 ± 6 mm Hg, p < 0.01) but not in the volume
overload group (139 ± 7 mm Hg, p = NS) compared with
values in normal subjects (117 ± 7 mm Hg). Left ventricular end-diastolic pressure was significantly increased in
both pressure overload (23 ± 3 mm Hg, p < 0.001) and
volume-overload (24 ± 2 mm Hg) groups compared with
values in normal subjects (10 ± 1 mm Hg). Peak systolic
meridional stress occurred early in ejection before the appearance of significant wall thickening, whereas at endejection when wall thickness was maximal, meridional stress
had decreased substantially even though left ventricular
pressure remained at or near peak levels. Values for left
ventricular peak and mean systolic stress were similar in
normal volume-overloaded and pressure-overloaded hearts.
End-diastolic wall stress, however, was increased in patients
with volume overload compared with values in the other
two groups.
200
,0,
~
180
I
I
160
I
I
I
I
140
I
I
I
I
I
I
N
E
120
~
2
I
I
I
I
I
I
w
a:
I-
80
(J)
.......... ANGlO STRESS
ECHO STRESS
I
100
(J)
(J)
0---0
I
I
...J
...J
<X
~
°I
I
I
I
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60
40
I
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20
Hypothesis relating wall stress and patterns of ventricular hypertrophy. These observations, coupled with
p"
I"
AI
p
0'--"'-----------=----TIME
Figure 6. Meridional wall stress calculated throughoutthe cardiac
cycle in a normal subject from simultaneous measurements of left
ventricular pressure, wall thickness and minor axis. Wall stress
calculated from angiographic (ANGlO) and ultrasonic (ECHO)
data show excellent agreement, withclose superimposition of stresstime plots constructed by the different methods. Similar agreement
was seen for pressure- and volume-overloaded ventricles. (Reproduced with permission from Grossman W, et al. [33].)
of the R wave of the electrocardiogram. Mean systolic meridional stress was determined by averaging values for meridional stress from end-diastole to end-systole,
Figure 7 shows the time course of changes in left ventricular pressure. wall thickness and meridional stress for
representative normal, pressure-overloaded and volumeoverloaded left ventricles. Left ventricular peak systolic
pressure was significantly increased in the pressure overload
previous experimental evidence (35-37) that systolic ventricular wall tension is a stimulus to hypertrophy, led Grossman et al. (33) to formulate the hypothesis depicted in Figure
8. According to this hypothesis, when the primary stimulus
to hypertrophy is left ventricular pressure overload, the resultant acute increase in peak systolic wall stress leads to
parallel replication of sarcomeres, wall thickening and concentric hypertrophy. The resultant wall thickening is sufficient to return peak systolic stress to normal, thus acting
as feedback inhibition of the hypertrophic process. Experimental support for this hypothesis has been found in the
investigations of Sasayama et al. (38), who produced acute
pressure overload hypertrophy by aortic banding in dogs,
and observed an initial increase in systolic wall stress immediately after banding that returned to normal within the
subsequent 2.5 weeks concomitant with a major increase in
left ventricular wall thickness. Sasayama et al. interpreted
the early increase in systolic wall stress as the stimulus for
subsequent hypertrophy. In contrast, when the primary stim-
A. NORMAL
N'~ 320
~
--.
~ 280
• WALL THICKNESS
···PRESSURE
U-"STRESS
~ 240
280
280
240
240
~
200
200
160
160
160
120
120
120
80
80
[~
40
10
'--"'T"""--r---"r---r-..., 5
TIME
TIME
TIME
Figure 7. Comparison of changes in left
ventricular pressure (solid dots), wall
thickness(open dots) and meridionalstress
(open squares) throughout the cardiaccycle
for representative normal (A), pressureoverloaded (B) and volume-overloaded (C)
left ventricles. Measurementsare plotted at
40 ms intervals. In the pressure-overloaded
ventricle (8), the markedly elevated systolic pressure is exactly counterbalanced by
increased wall thickness, with the result that
wall stress remains normal. In the volumeoverloaded ventricle (C), peak systolic stress
is normal, but end-diastolic stress is significantly increased. (Reproducedwith permission from Grossman W, et al. [33].)
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
JACC Vol. 5, No.6
June 1985:578- 658
63B
HYPOTHESIS
.,
Primary Stimulus
8 "
PRESSURE ~
Increased
OVERLOAD
Systolic Pressure
..
Increased
Systolicu ~
@, ,
VOLUME ~ Increased ----.. Increased
OVERLOAD
Diastolic Pressure
Diastolic u
8\,
"
,------> -
..........
""
" ..... .....
Parallel Addition..
Wall
~ CONCENTRIC
of New Myofibrils
Thickening
HYPERTROPHY
__ .... ---- ..... ,
\\
"
,
\
\
",
Series Addition ~ Chamber ......... ECCENTRIC
of New Sarcomeres
Enlargement
HYPERTROPHY
,,~
"
....
_-------------- - ' --'
ulus to hypertrophy is left ventricular volume overload ,
increased end-diastolic wall stress leads to series replication
of sarcomeres , fiber elongation, chamber enlargement and
eccentric hypertrophy (Fig. 8). Chamber enlargement leads
acutely to increased peak systolic wall stress, which in tum
causes wall thickening of sufficient magnitude to normalize
the systolic stress . Thus , both wall thickening and fiber
elongation contribute to the pattern of eccentric hypertrophy.
Neurohumoral Factors
Among the nonmechanical factors that have been implicated in the pathogenesis of myocardial hypertrophy are
genetic influences, the presence of processes that have a
deleterious influence on the myocardium (such as aging,
diabetes mellitus and cardiomyopathy), increased activity
of the renin-angiotensin system , increased circulating catecholamines or discharge of the cardiac sympathetic nerves,
thyroxine and growth hormone (39,40) .
Renin-angiotensin system. Angiotensin II has been
shown to stimulate myocardial DNA, RNA and protein synthesis (41) and thus is thought to play at least a permissive
role in the development of myocardial hypertrophy in hypertensive states in which circulating renin levels are elevated. Recent experiments (42) in liver cell preparations
have demonstrated that angiotensin II alters chromatin conformation in ways suggestive of enhanced transcriptional
activity, thus providing a cellular mechanism for the putative
myocardial hypertrophy effects of the renin-angiotensin system. Moreover, treatment of hypertensive subjects with
antihypertensive drugs such as hydralazine or minoxidil ,
which tend to elevate renin levels , fails to reverse left ventricular hypertrophy despite adequate control of blood pressure, whereas drugs such as alpha-methyldopa and captopril, which lower angiotensin II levels, cause left ventricular
Figure 8. Hypothesis relating wall stress and patterns of hypertrophy. (T = meridional stress. (Reproduced with permission from
Grossman W, et al. [33].)
hypertrophy to regress (43-47). The differential effects of
these agents on the myocardium may be related to factors
other than the renin-angiotensin system , such as hemodynamics, catecholamine release and direct stimulation of myocyte and connective tissue growth . Further study is needed
to define the role of renin or angiotensin, or both, in the
pathogenesis of myocardial hypertrophy in hypertension.
Increased circulating catecholamines. Several lines of
evidence have implicated catecholamines in the pathogenesis of cardiac hypertrophy (39,48-50). Exogenous catecholamines induced myocardial hypertrophy and hypertrophy of cardiac myocytes maintained in culture (51,52), and
myocardial catecholamine stores and turnover are altered in
the hypertrophic heart (53). Further , long-term administration of beta-adrenergic receptor antagonists has been shown
(54) to reduce myocardial growth in normal animals (rabbits).
In contrast, the contribution of catecholamines to the
development of myocardial hypertrophy in the setting of
systemic hypertension is uncertain . Most studies (55,56)
show that long-term administration of a beta-adrenergic receptor antagonist does not prevent or cause reversal of myocardial hypertrophy in hypertensive animals (rats), even when
blood pressure is lowered significantly. In addition , studies
of the effects of sympathetic denervat ion of the heart on the
development of myocardial hypertrophy have yielded conflicting results. Neonatal immunosympathectomy with nerve
growth factor antiserum does not prevent cardiac hypertrophy in the spontaneously hypertensive rat of the Okamoto
strain despite prevention of the hypertension and extensive
64B
OPARIL
PATHOGENESIS OF VENTRICULAR HYPERTROPHY
depletion of myocardial norepinephrine stores (57). Similarly , chemical sympathectomy with 6-hydroxydopamine
does not prevent the development of cardiac hypertrophy in
the deoxycorticosterone (acetate) (DOCA) sodium chloride
hypertensive rat, a model in which increased sympathetic
nervous system activity has been demonstrated. In contrast,
chemical sympathectomy with guanethidine has been shown
to prevent exercise-induced myocardial hypertrophy in normotensive rats (58). Alpha-methyldopa, a centrally acting
antihypertensive drug that has a sympatholytic effect on the
heart, can prevent or reverse myocardial hypertrophy
(43,44,46). This agent also has effects on systemic hemodynamics, myocardial contractility and the renin-angiotensin system, which complicate the interpretation of these data
(39). In contrast, c1onidine, an agent that has a mechanism
of action similar to that of alpha-methyldopa, does not prevent or reverse myocardial hypertrophy in the spontaneously
hypertensive rat despite significant reductions in blood pressure and heart rate (59) . Systemic vasodilators such as hydralazine or minoxidil , which cause reflexly mediated myocardial stimulation, fail to reverse or even exacerbate
myocardial hypertrophy despite adequate control of blood
pressure (43,49). Thus, the role of catecholamines in the
pathogenesis of hypertension-related myocardial hypertrophy is uncertain, despite the fact that activity of the cardiac
sympathetic nerves, as assessed by turnover and synthesis
of norepinephrine in the myocardium , is increased in several
animal models of hypertension.
Recently, a soluble protein-synthesis-stimulating factor
that appears to be a protein has been isolated from the
hypertrophied myocardium of the spontaneously hypertensive rat (60) . Further study of this and other myocardial
growth factors may provide a biochemical basis for genetically based myocardial hypertrophy.
JACC Vol. 5, No.6
June 1985:57B-65B
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