Katz defines heart failure
as a clinical syndrome in which heart disease reduces
cardiac output, increases venous pressure (hemodynamic
abnormality), and is accompanied by molecular abnormalities
that cause progressive deterioration of the failing
heart and premature myocardial cell death. Therapy for
heart failure involves knowledge of its increasingly
complex physiology and pharmacology, and how these modify
functional and proliferative signaling.
Functional and proliferative signaling are not two distinct
mechanisms, and the key to understanding the management
of heart failure requires understanding the crossovers
between these mechanisms. |
|
| Functional signaling, specifically
the neurohumoral response, has at least three components.
First is the short-term functional response, that is,
the hemodynamic defense reaction. Factors involved in
this response are salt and water retention mediated
by angiotensin II, vasopressin, and aldosterone; vasoconstriction,
mainly norepinephrine and alpha-adrenergic, angiotensin
II, endothelin, and to some extent vasopressin; and
cardiac stimulation, beta-adrenergic stimulation of
the heart. Second is the proliferative response, that
is, the hypertrophic response that produces an altered
phenotype and apoptosis, stimulated by cell deformation,
cytoskeletal abnormalities, changes in cell adhesion
molecules and various growth factors. Most mediators
of the hemodynamic defense reaction also modify proliferative
signaling. Third is the inflammatory response, mediated
by cytokines, which includes a long-term proliferative
response. |
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Proliferative
Signaling and Adaptive Hypertrophy |
A stimulus of cardiac overload results in hypertrophy,
mediated by cell deformation, growth factors, cytokines,
and calcium and neurohumoral mediators. This begins
as adaptive growth, which yields more sarcomeres and
thereby reducing the load on each sarcomere. The hypertrophic
response initially is totally adaptive and can normalize
wall stress. However, maladaptive hypertrophy, which
accelerates cell death and increases the load on the
remaining cells, is also occurring and causes patients
with heart failure continue to deteriorate.
Four factors, at least, are mechanistically involved
in overload-induced cardiomyopathy. These are necrosis,
a functional response; altered phenotype and apoptosis,
a proliferative response; and cytokine effects, primarily
a proliferative response. In the functional response
there is energy starvation due to increased energy demands
on the individual cells, decreased energy supply, reduced
coronary flow, and mitochondrial damage. Membrane damage
is caused by oxygen free radicals and lipid accumulation
that causes cell death. In the altered phenotype, the
heart changes size and shape. At the molecular level,
there is reversion to the fetal phenotype, which reduces
contractility and relaxation and impairs energy production.
Cells change in size and shape, with cell elongation
or remodeling being the most important, which increases
energy demand by the Law of LaPlace and cell thickening
that reduces energy supply due to the change in architecture.
Apoptosis, a regulated process that does away with old
cells as new cells are grown, is particularly deadly
in the heart where adult cardiac myocytes do not normally
divide. If these cells are stimulated to grow, either
by cytoskeletal deformation, growth factors, or neurohumoral
factors, the cardiac myocytes become larger. This shortens
the life expectancy of the cells, and they become susceptible
to necrosis and probably apoptosis. This maladaptive
hypertrophy occurring in the cells of the patient with
heart failure is the major problem in heart failure.
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Phenotypes
of Hypertrophy |
Familial hypertrophic cardiomyopathy,
volume overload, dilated cardiomyopathies, pressure
overload, regional wall abnormality caused by myocardial
infarction, and athlete’s heart are different phenotypes
of hypertrophy. At the molecular level there is exercise-induced
hypertrophy with changes in myosin ATPase and hypertensive
hypertrophy with overexpression of the beta myosin heavy
chain. At a cellular level, hypertrophy causes about
a two-fold increase in cell size. Different signal transduction
pathways also exist. Cell deformation is probably the
most important clinical factor causing hypertrophy.
When a cell is stretched it sends a signal that goes
into the nucleus and causes transcription factor activation.
MAP kinase pathways, intracellular regulatory systems,
are stimulated by different factors, including cell
deformation, growth factors, cytokines, and various
mediators of the neurohumoral response. Studies have
shown that different types of cell deformation produce
different types of activation of the proliferative signaling
MAP kinases and that there is a great deal of discrimination
between mechanical stress. Cytokine levels are significantly
elevated in patients with chronic heart failure as part
of an inflammatory response. The effect of the elevated
cytokines in heart failure is unclear, because cytokines
cause inflammation, cell proliferation, apoptosis, and
hypertrophy and activate a number of pathways. |
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Therapeutic
Approaches for Both Pathways |
Vasodilators are beneficial
in the short term with their functional response of
unloading the failing heart, increasing cardiac output
and reducing energy expenditure. However, the long-term
results with vasodilators are puzzling. The combination
of hydralazine and isosorbide dinitrate in the V-HeFT
I and II studies had a small beneficial effect that
was gone after five years. ACE inhibitors make patients
better over the long-term in the clinical trials. Angiotensin
receptor blockers are nearly as beneficial as the ACE
inhibitors. Amlodopine, a long-acting calcium channel
blocker, has been shown to be safe, but does not effect
survival. Alpha blockers, such as prazosin, probably
are harmful in the setting of heart failure. The short-acting
L-type calcium channel blockers should not be used as
they appear to cause significant harm, but there are
no long-term clinical trials.
The benefit seen with ACE inhibitors seems to be related
to crossover between functional and proliferative signaling.
Angiotensin is also a growth factor, and the SAVE trial
with enalapril showed that enalapril inhibited remodeling
in patients after a myocardial infarction. However,
pooled data from Greenberg and colleagues show that
although the ACE inhibitor initially blocked the growth
response, whereas in placebo patients left ventricular
mass continued to progressively increase. However, with
time the ACE inhibitor-treated patients also suffered
progressive hypertrophy and death. Treatment with an
ACE inhibitor seems to be only palliative. |
 |
| Figure
1. Beta blockers reduced heart size compared to
an increase in wall thickness and mass with placebo
and an ACE inhibitor in the US Carvedilol Trials. |
| Click
to enlarge |
|
The beta blocker
bisoprolol was associated with a 32% mortality reduction
in the CIBIS II trial and metoprolol was associated
with a 34% mortality reduction in the MERIT HF trial.
Metoprolol adds about six months to survival. Beta blockers
were initially used to reduce the energy demands of
the failing heart, as the drugs are negatively chronotropic,
inotropic, and lusotropic. However, beta blockers have
recently been shown to also inhibit proliferative signaling.
The growth signals mediated by beta adrenergic stimulation
of the heart have been shown to be quite harmful to
the heart. Figure 1 shows the reduction in heart size
after four months in patients treated with a beta blocker
compared to the increase in wall thickness and mass
in patients treated with placebo and an ACE inhibitor
in the US Carvedilol Trials. |
| |
| Figure
2. Mechanisms by which proliferative signaling
can be activated by cross-overs from sympathetic
signaling. |
| Click
to enlarge |
| |
| Figure
3.Classic proliferative signaling: the mitogenic
MAP kinase pathway |
| Click
to enlarge |
|
Clearly, beta
adrenergic stimulation must be thought of also in terms
of modifying transcriptional regulation. It is very
clear that there are many crossovers between functional
signaling, the complicated signal transduction pathway
that alters function of existing elements, and proliferative
signaling that alters gene transcription. Figure 2 illustrates
an example of classical functional signaling through
sympathetic stimulation, which has at least five different
mechanisms by which it can alter gene expression. Figure
3 illustrates an example of classical proliferative
signaling, that is, the classic mitogenic MAP kinase
pathway. Effective therapy must address both of these
pathways. A beta blocker is potentially inhibiting mechanisms
in the pathways and is thus potentially beneficial for
the patient with heart failure.
Spironolactone was surprisingly shown in the RALES trial
to reduce mortality by 32% in patients with Class III-IV
heart failure, adding about one year to their lifespan.
The mechanism for this effect is not clear. An effect
on oxygen free radicals has been proposed, but there
is also an antiproliferative effect. Aldosterone has
been shown to have a proliferative effect, and spironolactone
blocks aldosterone from binding to its receptor. Endothelin
blockers, not approved for clinical use, have been shown
to improve long-term survival in an experimental model
of heart failure. Interestingly, in the animals with
a large myocardial infarction treated with an endothelin
blocker there was less cell growth and less maladaptive
hypertrophy.
The clinical trials from the last ten years have shown
that the signal transduction systems have negative effects
and that blocking the neurohumoral responses is beneficial.
Crossovers between the systems exist and must be addressed
therapeutically. Current therapy for heart failure should
include an ACE inhibitor or angiotensin receptor blocker
to maintain myocardial function, a beta blocker to address
the effects of the sympathetic nervous system, and spironolactone
to block aldosterone. Perhaps an endothelin blocker
and a vasopressin blocker will be shown to be beneficial
in clinical heart failure. There may also be new drugs
that block other maladaptive functions of the proliferative
response. |
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