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| Dynamic Plasticity of the Ventricle:
Myocyte Hypertrophy, Death and Hyperplasia in Remodeling
the Heart |
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Edmund H. Sonnenblick, M.D.
Albert Einstein College
of Medicine
New York, New York |
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| Ventricular remodeling,
a temporal change in the composition of the wall and
the shape of the ventricle, is central to many aspects
of the development of disease and represents potential
therapeutic opportunities. Some of the mediators of
remodeling include cardiac overload, myocyte loss, myocyte
proliferation, alterations in connective tissue, and
vascular alteration. |
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Increased wall thickness
is due to cell widening, which can occur under stress
such as systolic overload. Cell lengthening is caused
by physiologic alterations in sarcomere length or by
the addition of sarcomeres. Cell loss (apoptosis, necrosis)
and slippage (displacement) also contribute to hypertrophy.
Ventricular dilation results in increased wall tension
as a function of increased volume. Moreover, myocardial
function can be greatly altered by changing filling
characteristics. Diastolic recoil plays an important
role in ventricular filling and control of cardiac output
and can be lost as a result of cardiac dilation. Inadequate
mitral valve closure and mitral regurgitation occurs
as the heart becomes more spherical. The renin angiotensin
system (RAS) is activated secondary to myocardial stretch,
which causes cell death to be more active. Although
cardiac dilation is initially an adaptive process, it
results in progressive cell death mediated by RAS activation.
The pressure volume curve is altered (increased volume
with a stiffer curve) due to the globular shape of the
heart resulting from chronic dilation. Diastolic recoil
is lost as a result of the stiffer curve, which increases
the filling pressures. The volume change can be fully
explained by the changes in sarcomere length. Chronic
dilation causes displacement of cells and sarcomeres
in opposite directions, and this slippage contributes
to the increase in volume.
In the setting of myocardial infarction (MI), a smaller
infarct does not affect heart size, but a larger infarct
results in alteration of the remaining part of the wall,
with a shift to the right of the pressure volume curve.
After a MI, there is a slight fall in pressure in systole,
an increase in radius, a decrease in wall thickness,
and about a 25% increase in systolic wall stress. In
diastole, there is a large increase in pressure from
about 3 to about 20-25 and a large increase in diastolic
wall tension. The major abnormal load post-MI is in
the diastolic filling of the heart. Eccentric hypertrophy,
an increase in cell length, is the major consequence
of heart failure and is seen after a large infarct.
Destruction of connective tissue due to ischemia has
been shown to contribute to hypertrophy by Sonnenblick
and colleagues and other investigators, yet remains
an unexplored area. |
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Apoptosis, the programmed removal of cells that are
damaged or no longer needed, is an active process in
which the cell destroys itself and the particles of
the cell are absorbed locally without inflammation.
In the setting of acute MI, apoptosis is the first event
and is seen within hours. Ultimately, necrosis may be
superimposed on the apoptosis, that is, necrosis may
kill cells that began as apoptotic but lost sufficient
energy. Apoptosis in the non-infarct area of the heart
is turned on by the massive increase in diastolic filling
pressure. Whether or not this can cause heart failure
is controversial. Some work in mice showing that with
a sufficient degree of apoptosis that it is possible
to produce ventricular dilation. However, in the rat
model it has been shown that necrosis is the major consequence
of marked coronary narrowing and limited blood flow.
With aging, necrosis seems to be the major process,
which leads to slippage and increased volume leading
to stretch and as a consequence apoptosis.
In isolated papillary muscle, Sonnenblick and colleagues
showed that stretch induced apoptosis and, interestingly,
an increase in reactive oxygen species. The addition
of a nitric oxide donor reduced the reactive oxygen
species and apoptosis. Further, the cell surface death
signal FOS was activated in the cells that went on to
apoptosis.
Pathological overloading has been shown to upregulate
components of the RAS, including converting enzyme activity,
renin, angiotensin I, and angiotensin II. Further, angiotensin,
a major producer of reactive oxygen species, has been
shown to augment apoptosis. Stretch increases levels
of angiotensin II and p53, which is central to the evolution
of apoptosis. Angiotensin II causes apoptosis through
angiotensin and reactive oxygen species. Additionally,
angiotensin II damages DNA, which increases p53 and
local enhancement of the RAS.
An intracellular model shows how stretch and dilation
kills cells and augments dilation. Angiotensin increases
p53 and stretch increases protein kinase C and phosphorylation
of p53, which results in augmentation of apoptosis,
increased p53, further apoptosis and cell growth.
In the setting of diabetes, despite the fact that the
heart is 25% smaller in size, there is cellular hypertrophy
with its attendant consequences. Apoptosis seems to
be responsible for cell loss. The angiotensin system
plays a role in this process, as shown by elevated levels
of angiotensin that are blocked by losartan, and it
may be that p53 is glycosylated. Apoptosis is elevated
in the myocyte, endothelial cells and fibroblasts in
diabetes or diabetes with hypertension in heart failure.
Interestingly, the addition of hypertension to diabetes
increases necrosis, angiotensin and reactive oxygen
species. |
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| In the hypertrophied human
heart, there are more cells in terms of number than
in the normal heart. All the processes of mitosis, meiosis
and cytokinesis have been clearly demonstrated in humans.
It is unknown whether cell division contributes positively
or negatively to the disease process. Work in isolated
cells by Sonnenblick and colleagues has shown that there
is tremendous heterogeneity of function within the heart.
The degree to which this is due to hypertrophy or hyperplastic
cells is unknown. Another aspect is that telomeres become
shorter as a result of cell division. |
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