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1 Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, and 2 Division of Cardiology, Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07101-1709; and 3 Department of Internal Medicine, Cardiovascular and Immunological Sciences, University of Federico II, 80131 Naples, Italy
LEFT
VENTRICULAR (LV) hypertrophy (cardiac hypertrophy) is generally
considered a compensatory response of the heart to a variety of
stimuli, most commonly altered workload. Although the most common cause
of cardiac hypertrophy is essential hypertension in Western countries,
virtually all forms of cardiac diseases, including valvular
dysfunction, coronary artery disease, and arrhythmias, can stimulate
development of cardiac hypertrophy. Hypertrophy also occurs in several
systemic diseases, such as endocrine disorders and chronic renal
disease, in response to neural/humoral factors, independent of load.
More recently, it has been determined that hypertrophy occurs through
stimulation or deletion of specific signaling pathways (17, 32,
38). Importantly, however, it remains to be established whether
hypertrophy is adaptive or maladaptive.
It is well known that mechanical loading is one of the most critical
determinants of cardiac muscle mass (38). For example, right ventricular pressure overload induced by pulmonary artery banding
causes right ventricular hypertrophy, whereas the papillary muscle
undergoes atrophy when it is unloaded by transection of the chordae
tendineae (13). According to Laplace's law, increased wall thickness of the LV chamber reduces the wall stress, thereby reducing oxygen consumption in the heart. According to this view, development of cardiac hypertrophy can be considered as an adaptive response, and the impairment of this compensatory mechanism can lead to
transition from cardiac hypertrophy to LV dysfunction. For instance,
Meguro et al. (29) have demonstrated, using a mouse model
of pressure overload, that attenuation of cardiac hypertrophy by
administration of cyclosporine A, an inhibitor of
Ca2+-regulated phosphatases (calcineurin), was associated
with increased mortality of the animals because of heart failure. This
result supports the concept that cardiac hypertrophy is a beneficial compensatory mechanism that protects the heart in the face of increased
cardiac workload.
Epidemiological studies have demonstrated, however, that chronic
cardiac hypertrophy is a major independent risk factor for the
morbidity and mortality in the general population (33,
49), in patients with essential hypertension (10, 21,
48), and also in a variety of clinical settings (5, 25,
35). In fact, whereas cardiac hypertrophy is initially
compensatory, the continued presence of hypertrophy leads to dilated
cardiomyopathy, heart failure, ischemic heart disease, and
sudden death (22, 23). The LV diastolic and systolic
dysfunction and subsequent development of congestive heart failure
start from hypertrophic remodeling of the heart. Accumulation of
fibrillar collagen in the interstitial space of the hypertrophied LV
accounts for the abnormal myocardial stiffness and for the impairment
of diastolic function (19, 20, 36), which precedes the
occurrence of the systolic dysfunction. Chronic pressure overload
increases cardiac myocyte apoptosis through increases in the
ratio of proapoptotic (such as bax) and
antiapoptotic (such as bcl-2) gene expression (12), which may lead to systolic LV dysfunction.
Impaired subendocardial coronary reserve is one of the hallmarks of
cardiac hypertrophy (28). Structural variables proposed to
explain reduced subendocardial coronary reserve include 1) an inadequate growth of the capillary vascular bed while ventricular mass is increasing (6, 7, 37), 2) a reduction
in the luminal cross-sectional areas of resistance vessels (28,
45), 3) an increase in the medial area of resistance
vessels (2, 8, 46, 52), and 4) failure of the
large epicardial conductance arteries and cross-sectional area of the
vascular bed to enlarge in proportion to the degree of hypertrophy
(27, 42, 51). In our laboratory, we have studied models of
both right ventricular and LV severe pressure overload hypertrophy
(16, 34), where subendocardial coronary reserve was
reduced >50% during adenosine-induced vasodilatation. Despite the
extensive hypertrophy, capillary density was equally reduced by only
10-15% in endo-, mid-, and epicardial LV regions compared with
control dogs, whereas increased capillary cross-sectional area resulted
in no change in capillary surface area/myocyte volume or volume
percentage capillary space (3). Thus the mechanism of
reduced subendocardial reserve is complex and can be explained only
partially by structural alterations in the chronic setting where
angiogenesis also occurs. This was confirmed in our laboratory
(16) by demonstrating that the reduction in subendocardial
reserve in LV hypertrophy is markedly attenuated, when compressive
forces were mitigated, by unloading the heart. Perivascular fibrosis
and medial thickening of intramyocardial coronary arteries also
account, in part, for the impairment of coronary vasodilator reserve,
which is commonly seen in cardiac hypertrophy (2, 30).
Endothelium-dependent and -independent coronary vasorelaxation are also
impaired in cardiac hypertrophy (18). Finally, cardiac
hypertrophy compromises the neural control of coronary blood flow
through alterations of cardiopulmonary baroreceptor functions
(47). Thus the reduction of LV mass must be considered to
be a primary end point for the treatment of patients with cardiac
hypertrophy. In fact, several studies (33) have demonstrated that the regression of cardiac hypertrophy appears to be a
favorable prognostic marker independent of the treatment-induced reduction in blood pressure.
Although the aforementioned salutary and detrimental aspects of cardiac
hypertrophy seem contradictory, one important issue is the difference
in the role of hypertrophy in response to acute versus chronic loads.
Clearly, the normal heart cannot develop the same systolic pressure as
can a hypertrophied heart. Patients with significant aortic stenosis
often have pressure gradients over 100 mmHg and with stress or
vasoconstrictors may achieve systolic pressures >300 mmHg. This load
cannot be tolerated in a nonhypertrophied heart. In fact, the lack of
ability to mount a compensatory hypertrophic response may argue for a
poor prognosis. This must be distinguished from the chronic effects of
severe hypertrophy that may be deleterious as we discussed above.
Although it is established that chronic severe cardiac hypertrophy
enhances cardiovascular risk, our hypothesis is that acute cardiac
hypertrophy is compensatory. At variance with this hypothesis, recent
studies have demonstrated that inhibition of load-induced cardiac
hypertrophy may lead to preserved cardiac function despite sustained
elevation of the LV wall stress (14, 15). In transgenic mice with cardiac-specific expression of a carboxyl terminal peptide of
G Figure 1 summarizes the role of
representative molecules in cardiac hypertrophy and apoptosis.
Each signaling molecule does not necessarily affect cardiac hypertrophy
and apoptosis in the same direction. It should be noted
that the role of each signaling molecule is not identical when it is
studied by using distinct upstream stimuli. For example, although mice
deficient in MEKK1 (the upstream kinase of c-Jun NH2-
terminal kinase) exhibited pronounced dilation of cardiac chambers,
reduction of LV ejection fraction, increased apoptosis, and
premature death in cardiac hypertrophy in response to pressure overload
(39), cardiac hypertrophy and development of
cardiomyopathy are attenuated in the same mice when hypertrophy was
induced by cardiac-specific overexpression of G
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REFERENCES
q (Tg-GqI), which specifically inhibits Gq-mediated signaling (1), as well as in mice deficient in dopamine
-hydroxylase gene (Dbh
/) (44), resulting in lack of
endogenous norepinephrine and epinephrine, pressure overload caused a
blunted hypertrophic response. In these studies, although wall stress
was completely normalized in banded wild-type mice due to the induction
of adequate hypertrophy, it remained elevated in banded Tg-GqI mice due
to lack of adequate hypertrophy. Interestingly, wild-type mice with normalized LV wall stress showed an increase in chamber dimensions and
a progressive deterioration of the LV function. By contrast, indexes of
LV function in Tg-GqI and Dbh/ mice showed significantly less
deterioration. These data suggest that cardiac hypertrophy may be
simply maladaptive. It should be noted, however, that although modification of the signaling mechanism in those cases caused both
reduction of cardiac hypertrophy and maintenance of cardiac function,
reduction of cardiac hypertrophy could be an epiphenomenon. In other
studies, some forms of cardiac hypertrophy, including those induced by
cardiac-specific overexpression of extracellular signal-regulated
protein kinase (ERK) (9), Akt (11, 41), or
phosphoinositide-3 kinase (40), are adaptive and do not
show long-term decompensation. Thus it remains to be elucidated
if the maintenance of cardiac function seen in Tg-GqI and Dbh/ mice
is mediated through inhibition of cardiac hypertrophy. We have recently
(43) found that mice deficient in adenylyl cyclase type 5, a major isoform of adenylyl cyclase in the heart, can tolerate pressure
overload, thereby exhibiting well-maintained LV ejection fraction and
LV chamber size compared with wild-type littermates. In
contrast, we have also shown (39) that mitogen-activated protein kinase and ERK kinase kinase 1 (MEKK1) knockout mice are more
susceptible to pressure overload and develop cardiac dysfunction compared with the control wild-type (MEKK1+/+) mice. These studies suggest that modifying a particular signaling mechanism could exhibit
profound effects on the maintenance of cardiac function in response to
hemodynamic overload than normalizing the wall stress. In this regard,
we should keep in mind that cardiac hypertrophy occurs in response to a
wide variety of stimuli, each of which activates an intricate network
of signaling molecules, involving protein kinases, protein
phosphatases, and other second messengers (26, 32, 38).
These molecular pathways not only mediate cardiac hypertrophy but are
also responsible for activation of deleterious mechanisms for the heart
(i.e., apoptosis and impairment of contractility), which
results in development of LV dysfunction and heart failure
(4). If one signaling molecule stimulates both hypertrophy
and cell death, inhibiting such molecule would reduce cardiac
hypertrophy and, at the same time, maintain cardiac function, thereby
showing beneficial effects. In contrast, if another signaling molecule
stimulates cardiac hypertrophy and cell survival, inhibiting such
molecule may not be necessarily beneficial because it could potentially
promote cell death and cardiac dysfunction despite reduction in cardiac
hypertrophy. Therefore, it is important to identify which molecular
mechanisms make cardiac hypertrophy good or bad. Furthermore, the
important target of treatment of cardiac hypertrophy is not necessarily the reduction of LV mass itself but rather may be the correction of the
molecular pathways that account for the cardiac hypertrophy-related complications and/or the enhancement of the activity of cellular signals mediating cytoprotective actions.
q (31).
Cardiac function of some molecules remains unclear because experimental
results obtained from loss of function studies and those from gain of
function studies have shown contradictory results (24,
50). It is possible that the extent and the timing of expression
of the molecule significantly affect the function of the molecule in a
given pathological condition. For example, it is possible that one
molecule may mediate hypertrophy alone in the normal heart, whereas the
same molecule may mediate cell survival when it is activated in a heart
that already has hypertrophy. In this regard, it will be important to
establish the conditional expression system to precisely control both
expression levels as well as the timing of expression of the molecule
of one's interest.
View larger version (22K):
[in a new window]
Fig. 1.
Physiological hypertrophy [compensated left ventricular
(LV) hypertrophy] and pathological hypertrophy (decompensated LV
hypertrophy) are caused by a balance between the cell death-promoting
mechanism and the cell survival mechanism. Although many signaling
molecules listed in the text are involved in cardiac hypertrophy, some
molecules promote cell death, thereby causing pathological hypertrophy,
whereas other molecules promote cell survival, thereby causing
physiological cardiac hypertrophy. PKA, protein kinase A; PKC, protein
kinase C; CaMK, Ca2+/calmodulin-dependent protein kinase;
ERK5, extracellular signal-regulated protein kinase 5; MEKK1,
mitogen-activated protein kinase kinase kinase 1; JNK, c-Jun
NH2-terminal kinase; NF-AT3, nuclear factor of activated T
cells 3; PI3K, phosphoinositide 3-kinase; CREB, cAMP response element
binding protein; STAT3, signal transduction and activation of
transcription 3.
A number of studies performed in the last decade have demonstrated that the development of cardiac hypertrophy is a complex process involving changes in hemodynamics, genetic background, neurohormonal activation, growth factors, and cytokines, which stimulate different signaling pathways resulting in increases in cardiac myocyte cell size, sarcomere assembly, and induction of the "fetal"-type cardiac genes (reviewed in Refs. 32 and 38). It is likely that cardiac hypertrophy in each patient possesses a distinct phenotype depending on how cardiac hypertrophy is stimulated. Therefore, a new challenge in the treatment for cardiac hypertrophy is 1) to better characterize the different phenotypes of cardiac hypertrophy caused by distinct pathological stimuli, 2) to understand the relative contribution of each biochemical pathway in the pathogenesis of different forms of cardiac hypertrophy, and finally, 3) to find molecular markers specifically associated with the different phenotypes of cardiac hypertrophy to evaluate the effectiveness of the treatment of cardiac hypertrophy. Therefore, we propose that we should preserve the beneficial component of cardiac hypertrophy and target detrimental components when we treat patients with cardiac hypertrophy. The prognosis of chronic cardiac hypertrophy patients can be affected significantly by modulation of the signaling mechanisms rather than reduction of cardiac hypertrophy itself. Therefore, what we should treat in patients with chronic cardiac hypertrophy may be the signaling mechanisms mediating cardiac hypertrophy, which have more pronounced effects upon cell survival and death of individual cardiac myocytes. Precise understanding of the function of each signaling molecule in the heart and identifying how and when those signaling molecules are activated or inactivated will be essential to better control cardiac function and survival of the patient.
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ACKNOWLEDGEMENTS |
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This work is supported by National Institutes of Health Grants HL-59139, HL-33107, HL-33065, HL-65182, HL-65183, AG-14121, HL-69020, HL-67724, and HL-67727 and American Heart Association (AHA) National Grant 9950673N. C. Morisco is a recipient of AHA Mid Atlantic Postdoctoral Fellowship.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. F. Vatner, Dept. of Cell Biology and Molecular Medicine, Univ. of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Ave., MSB G-609, Newark, NJ 07101-1709 (E-mail: vatnersf{at}umdnj.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00990.2002
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Cardiac hypertrophy in early hypertension.
Am J Cardiol
44:
964-969,
1979[Web of Science][Medline].
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