Hypertrophy represents an increase
in cell size and with it an increase in the amount of functioning tissue mass
(Fig. 5.2). It results from an increased workload imposed on an organ or body
part and is commonly seen in cardiac and skeletal muscle tissue, which cannot
adapt to an increase in workload through mitotic division and formation of more
cells. Hypertrophy involves an increase in the functional components of the
cell that allows it to achieve equilibrium between demand and functional
capacity. For example, as muscle cells hypertrophy, additional actin and myosin
filaments, cell enzymes, and adenosine triphosphate (ATP) are synthesized.
Hypertrophy may occur as the result
of normal physiologic or abnormal pathologic conditions. The increase in muscle
mass associated with exercise is an example of physiologic hypertrophy.
Pathologic hypertrophy occurs as the result of disease conditions and may be
adaptive or compensatory. Examples of adaptive hypertrophy are the thickening
of the urinary bladder from longcontinued obstruction of urinary outflow and
the myocardial hypertrophy that results from valvular heart disease or
hypertension. Compensatory hypertrophy is the enlargement of a remaining organ
or tissue after a portion has been surgically removed or rendered inactive. For
instance, if one kidney is removed, the remaining kidney enlarges to compensate for the loss.
The initiating signals for
hypertrophy appear to be complex and related to ATP depletion, mechanical
forces such as stretching of the muscle fibers, activation of cell degradation
products, and hormonal factors. In the case of the heart, initiating signals
can be divided into two broad categories:
•
Biomechanical
and stretch-sensitive mechanisms
• Neurohumoral
mechanisms that are associated with the release of hormones, growth factors,
cytokines, and chemokines.
Internal stretch-sensitive
receptors for the biochemical signals and an array of membrane-bound receptors
for the specific neurohumoral ligands, such as IGF-1 and epidermal growth
factor (EGF), activate specific signal transduction pathways. These pathways
control myocardial growth by altering gene expression to increase protein
synthesis and reduce protein degradation, thereby causing hypertrophic
enlargement of the heart. A limit is eventually reached beyond which further
enlargement of the tissue mass can no longer compensate for the increased work
demands. The limiting factors for continued hypertrophy might be related to
limitations in blood flow. In hypertension, for example, the increased workload
required to pump blood against an elevated arterial pressure in the aorta
results in a progressive increase in left ventricular muscle mass and need for
coronary blood flow.
There continues to be interest in
the signaling pathways that control the arrangement of contractile elements in myocardial
hypertrophy. Research suggests that certain signal molecules can alter gene
expression controlling the size and assembly of the contractile proteins in
hypertrophied myocardial cells. For example, the hypertrophied myocardial cells
of well-trained athletes have proportional increases in width and length. This
is in contrast to the hypertrophy that develops in dilated cardiomyopathy, in
which the hypertrophied cells have a relatively greater increase in length than
width. In pressure overload, as occurs with hypertension, the hypertrophied
cells have greater width than length. It is anticipated that further
elucidation of the signal pathways that determine the adaptive and nonadaptive
features of cardiac hypertrophy will lead to new targets for treatment.
