Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ. The hypertrophied organ has no new cells, just larger cells. The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components. Cells capable of division may respond to stress by undergoing both hyperplasia (described later) and hypertrophy, whereas in non dividing (e.g., myocardial fibers) increased tissue mass is due to hypertrophy. In many organs hypertrophy and hyperplasia may coexist and contribute to increased size.

Hypertrophy can be physiologic or pathologic; the former is caused by increased functional demand or by stimulation by hormones and growth factors. The striated muscle cells in the heart and skeletal muscles have only a limited capacity for division, and respond to increased metabolic demands mainly by undergoing hypertrophy. The most common stimulus for hypertrophy of muscle is increased workload. For example, the bulging muscles of bodybuilders engaged in “pumping iron” result from enlargement of individual muscle fibers in response to increased demand. In the heart, the stimulus for hypertrophy is usually chronic hemodynamic overload, resulting from either hypertension or faulty valves (Fig. 1). In both tissue types the muscle cells synthesize more proteins and the number of myofilaments increases. This increases the amount of force each myocyte can generate, and thus increases the strength and work capacity of the muscle as a whole.

Fig1. The relationship between normal, adapted, reversibly injured, and dead myocardial cells. All three transverse sections of the heart have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. The cellular adaptation shown here is myocardial hypertrophy (lower left), caused by increased blood pressure requiring greater mechanical effort by myocardial cells. This adaptation leads to thickening of the left ventricular wall (compare with the normal heart). In reversibly injured myocardium (illustrated schematically, right), there are functional alterations, usually without any gross or microscopic changes but sometimes with cytoplasmic changes such as cellular swelling and fat accumulation. In the specimen showing necrosis, a form of cell death (lower right), the light area in the posterolateral left ventricle represents an acute myocardial infarction caused by reduced blood flow (ischemia).

The massive physiologic growth of the uterus during pregnancy is a good example of hormone-induced enlargement an organ that results mainly from hypertrophy of muscle fibers (Fig. 2). Uterine hypertrophy is stimulated by estrogenic hormones acting on smooth muscle through estrogen receptors, eventually resulting in increased synthesis of smooth muscle proteins and an increase in cell size.

Fig2. Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus, compared with C, large plump cells from the gravid uterus, at the same magnification.

Mechanisms of Hypertrophy

Hypertrophy is the result of increased production of cellular proteins. Much of our understanding of hypertrophy is based on studies of the heart. There is great interest in defining the molecular basis of hypertrophy since beyond a certain point, hypertrophy of the heart becomes maladaptive and can lead to heart failure, arrhythmias and sudden death (Chapter 11). There are three basic steps in the molecular pathogenesis of cardiac hypertrophy:

• The integrated actions of mechanical sensors (that are triggered by increased workload), growth factors (including TGF-β, insulin-like growth factor 1 [IGF1], fibroblast growth factor), and vasoactive agents (e.g., α-adrenergic agonists, endothelin-1, and angiotensin II). Indeed, mechanical sensors themselves induce production of growth factors and agonists (Fig. 3).

• These signals originating in the cell membrane activate a complex web of signal transduction pathways. Two such biochemical pathways involved in muscle hypertrophy are the phosphoinositide 3-kinase (PI3K)/ AKT pathway (postulated to be most important in physiologic, e.g., exercise-induced, hypertrophy) and signaling downstream of G-protein–coupled receptors (induced by many growth factors and vasoactive agents, and thought to be more important in pathologic hypertrophy).

• These signaling pathways activate a set of transcription factors such as GATA4, nuclear factor of activated T cells (NFAT), and myocyte enhancer factor 2 (MEF2). These transcription factors work coordinately to increase the synthesis of muscle proteins that are responsible for hypertrophy.

Fig3. Biochemical mechanisms of myocardial hypertrophy. The major known signaling pathways and their functional effects are shown. Mechanical sensors appear to be the major triggers for physiologic hypertrophy, and agonists and growth factors may be more important in pathologic states. ANF, Atrial natriuretic factor; GATA4, transcription factor that binds to DNA sequence GATA; IGF1, insulin-like growth factor; NFAT, nuclear factor activated T cells; MEF2, myocardial enhancing factor 2.

Hypertrophy is also associated with a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α isoform of myosin heavy chain is replaced by the β isoform, which has a slower, more energetically economical contraction. In addition, some genes that are expressed only during early development are reexpressed in hypertrophic cells, and the products of these genes participate in the cellular response to stress. For example, the gene for atrial natriuretic factor is expressed in both the atrium and the ventricle in the embryonic heart, but it is down-regulated after birth. Cardiac hypertrophy is associated with increased atrial natriuretic factor gene expression. Atrial natriuretic factor is a peptide hormone that causes salt secretion by the kidney, decreases blood volume and pressure, and therefore serves to reduce hemodynamic load.

Whatever the exact cause and mechanism of cardiac hypertrophy, it eventually reaches a limit beyond which enlargement of muscle mass is no longer able to cope with the increased burden. At this stage several regressive changes occur in the myocardial fibers, of which the most important are lysis and loss of myofibrillar contractile elements. In extreme cases myocyte death can occur. The net result of these changes is cardiac failure, a sequence of events that illustrates how an adaptation to stress can progress to functionally significant cell injury if the stress is not relieved.

To prevent such consequences, several drugs that inhibit key signaling pathways involving NFAT, GATA4, and MEF2 genes are in phase 1 or 2 clinical trials.

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