Cardiac hypertrophy is a process wherein there is an increase in chamber mass produced largely by an increase in the size of terminally differentiated cardiomyocytes. Although cardiomyocytes make up only one-third of the total cell number, they are responsible in aggregate for over 70 percent of cardiac volume. Cardiac hypertrophy may be reasonably categorized as either physiologic or pathologic Fig. 5-1).
Physiologic hypertrophy includes cardiogenesis during embryonic development, postnatal cardiac growth, a modest additional increase in heart size that evolves during senescence, and the increase in heart size that occurs in response to athletic conditioning. The earliest stage of cardiac growth in utero depends on a genetically determined developmental program, since it can occur in the absence of contractile activity. Subsequently, mechanical forces become increasingly important in the development of the normal cardiac phenotype. Throughout the embryonic period and for a few weeks after birth, cardiac growth occurs as a consequence of hyperplasia and hypertrophy of myocytes (see Chap. 9). Classically, adult myocytes have been described as terminally differentiated-that is, incapable of reentering the cell cycle. This issue is currently undergoing reexamination. It is critical to make a distinction between DNA synthesis and cell division. In the adult cardiomyocyte, DNA synthesis may clearly result in either multinucleation or polyploidy (an increase in the DNA content of a single nucleus). By contrast, there is little evidence that cardiomyocytes are capable of division under normal conditions after the early postnatal period.3,4 The capacity to reactivate hyperplasia in the terminally differentiated cardiomyocyte is an area of intense research interest, with potentially important therapeutic implications in the hypertrophied and failing heart.5
From birth to maturation, the mammalian heart undergoes a sixfold increase in mass. The normal heart/body weight ratio is species-specific. The largest hearts relative to body size occur in animals with survival requirements that depend on sustained exercise rather than on burst activity.6 In humans, intense, prolonged exercise training can produce an increase in cardiac mass. Isotonic exercise, such as running, produces eccentric hypertrophy, characterized by a normal ratio of wall thickness to dimension, whereas isometric exercise, such as weight lifting, stimulated concentric hypertrophy, associated with an increased ratio of wall thickness to dimension.7 Senescent animals and humans free of organic heart disease develop mild concentric left ventricular hypertrophy as a consequence of age-related decreases in the distensibility of the peripheral vasculature.8 The molecular, biochemical, and physiologic changes associated with physiologic hypertrophy differ both qualitatively and quantitatively from those that occur during pathologic hypertrophy. Physiologic studies in animal models and humans have demonstrated no substantial alterations in isolated muscle or intact heart function. There is also little evidence of alterations in the molecular determinants of excitation-contraction coupling. Most importantly, epidemiologic data fail to demonstrate adverse risk associated with the modest hypertrophy that occurs as a consequence of athletic conditioning. It is, therefore, important clinically to distinguish physiologic hypertrophy from hypertrophic cardiomyopathy in athletes (see Chap. 67).
Pathologic hypertrophy is an important adaptive response to abnormal global or regional increase in cardiac work. Initially, the increase in cardiac mass serves to normalize wall stress and permit normal cardiovascular function at rest and during exercise in compensated hypertrophy. If the stimulus for pathologic hypertrophy is sufficiently intense or prolonged, decompensated hypertrophy and heart failure ensue. Pathologic hypertrophy may be caused by pressure overloading, as in systemic or pulmonary arterial hypertension, left ventricular outflow obstruction, or aortic coarctation. Pressure overloading produces an increase in systolic wall stress and results in concentric ventricular hypertrophy. Volume overloading, as occurs in mitral or aortic regurgitation or as a result of arteriovenous fistulas, also produces pathologic hypertrophy. These latter conditions induce an increase in either diastolic wall stress (mitral regurgitation) or both systolic and diastolic wall stress (aortic regurgitation and arteriovenous fistulas) and result in eccentric left ventricular hypertrophy. Regional hypertrophy that occurs in viable myocardium adjacent to and remote from an area of infarction has the characteristics of eccentric hypertrophy.
There are exceptions to the principle that pathologic hypertrophy occurs as a result of excessive increases in external work. For example, hypertrophic cardiomyopathy is produced by point mutations of the sarcomeric proteins, in particular the ^-myosin heavy chain. These mutations result in massive asymmetric or concentric hypertrophy in the absence of augmented peripheral hemodynamic requirements (see Chap. 62). It is possible that the massive myofibrillar disarray that characterizes this genetic form of hypertrophy increases internal cardiac work, which, in turn, increased cardiac mass.9,10 Genetically engineered mice with cardiac-specific postnatal overexpression of the adrenergic receptor!! or targeted ablation of the phospholamban gene!^ have enhanced cardiac function throughout life but no significant increase in cardiac mass. By contrast, similar cardiac overexpression of the sarcoplasmic reticulum-binding protein calsequestrin in mice results in hypofunction of the heart, with decreased external work and substantial cardiac hypertrophy.13 Finally, tachycardia-induced heart failure in animal models and humans is associated with increased external cardiac work, decreased cardiac function, and no alteration in cardiac mass. These recent observations suggest a critical reexamination of the primary role of mechanotransduction in the etiology of pathologic hypertrophy.
Mechanisms for the Development of Cardiac Hypertrophy STIMULI AND SIGNAL TRANSDUCTION PATHWAYS
Dynamic or static stretch of neonatal or adult cardiomyocytes, papillary muscle, isolated heart, or intact heart produces increased cardiac protein synthesis and resultant cellular hypertrophy.14 The process by which stimuli in the physical domain activate intracellular growth-signaling pathways is known as mechanotransduction.15 There is evidence that this process may be accomplished in the cardiomyocyte by stretch-activated sarcolemmal ion channels, G protein-coupled receptors, NA+/H+ antiporters, tyrosine kinase-containing receptors, and/or an extracellular matrix-integrin linked pathway. These cell-surface mechanotransducers then activate cytosolic signal transduction pathways that initiate gene transcription and translation of increased quantities of protein Fig. 5-2). Important signal transduction pathways that are clearly activated by mechanical deformation include protein kinase C (PKC), mitogen activated protein (MAP) kinases, stress-activated protein kinase, and possibly cyclic adenosine monophosphate (cAMP)-dependent protein kinase.16 In particular, stretch of neonatal cultured cardiomyocytes produces G proteinmediated activation of membrane-bound phospholipase C, which, in turn, hydrolyzes phosphatidylinositol bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacylglycerol (DAG).
Diacylglycerol then activates PKC.17,18 Phosphorylation of downstream cytosolic and nuclear proteins and transcription factors by PKC is known to be of critical importance for growth in a number of cell types, while inositol triphosphate is an important modulator of cytosolic calcium homeostasis by the interaction with its receptor on the sarcoplasmic reticulum. Angiotensin II receptor coupling appears to play a critical role in the activation of phospholipase C;1920 however, Otj-adrenergic and endothelin receptor stimulation can also activate this pathway, with resultant hypertrophy in the neonatal cardiomyocytes and in transgenic mice.21-23
Current information suggests that mechanotransduction and a number of interrelated autocrine, paracrine, and endocrine effects of hormones and growth factors mediate cardiac hypertrophy24 Fig. 5-2). The resultant activation of multiple signal transduction pathways, which have demonstrable cross talk and considerable redundancy, provides a powerful mechanism by which the heart can respond to changing chronic hemodynamic requirements. A point of downstream convergence of multiple signal transduction pathways in the heart and noncardiac systems appears to be the phosphorylation of mitogen-activated protein kinase [MAPK, also known as extracellular signal regulated kinase (ERK)].25 Mammalian MAPKs are serine-threonine protein kinases that are activated by signal transduction pathways coupled to both phosphatidylinositol hydrolysis/PKC activation and receptor protein tyrosine kinases Fig. 5-2). Of particular importance to cardiac hypertrophy is the observation that important transcription factors (c-jun, c-myc, p62TCF) are known substrates of MAPK phosphorylation. Recently, transfection of an antisense nucleotide to MAPK was shown to prevent hypertrophy in cardiomyocytes. Information from noncardiomyocyte cell systems, neonatal and adult myocytes, and genetically engineered mice has demonstrated considerable complexity, redundancy, and cross talk among these and other intracellular signaling pathways in the development of the cardiac hypertrophy phenotype in response to stretch and other stimuli.26 In particular, ischemia, hypoxia, oxidative stress, neurohormones, and cytokines can activate downstream signaling and resultant nuclear transcriptional events, including cardiomyocyte hypertrophy and fibroblast hyperplasia.
Gotq-coupled receptors-which include angiotensin II, phenylephrine, endothelin, prostaglandin F2a, and thrombin-can induce hypertrophy of neonatal cardiomyocytes in culture in the absence of altered mechanical forces and in vivo in genetically engineered mice when the receptor is overexpressed.27
Cytokines were initially characterized by their pleiotropic effects upon the cellular components of the immune system. They have recently been implicated in normal and pathologic cardiac growth by a variety of in vitro and in vivo animal studies and by clinical investigation. Cytokines of the interleukin-6 and cardiotrophin family activate the gp130 cardiomyocyte transmembrane receptor and rapidly stimulate cytoplasmic Janus kinases (JAK); these, in turn phosphorylate other cytoplasmic proteins called signal transducers and activators of transcription (STAT). Various components of gp130 and JAK-STAT pathways have induced hypertrophy in vitro and in vivo when overexpressed in transgenic mice.28 By contrast interleukin-1 and tumor necrosis factor alpha (TNF-a) use a distinct pathway that involves activation of a phosphatidylcholine-specific phospholipase C with generation of diacylglycerol.29 These cytokines are elevated in the plasma of patients with congestive heart failure, and inhibition of their effects is a current therapeutic target for clinical heart failure. There is increasing evidence that stimulation of cell-surface tyrosine-kinase receptors can elicit a hyperplastic or hypertrophic response in neonatal cardiomyocytes. Both acidic and basic fibroblast growth factors (FGFs), which act as ligands for tyrosine-kinase receptors, can induce myocyte growth.30 Acidic FGF produces a hyperplastic response, whereas basic FGF stimulates an increase in protein synthesis with resultant hypertrophy.31 In contrast to its role in vascular smooth muscle growth, transforming growth factor beta (TGF-P) does not induce a growth response under these conditions.32
In addition to FGF and TGF-ft, insulin-like growth factor 1 (IGF-1) is expressed in the myocardium in response to pressure overload hypertrophy.33 These and other peptide growth factors [neural growth factor (NGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin] bind to receptor tyrosine kinases (RTK). These receptors undergo ligand-mediated homodimerization with resultant autophosphorylation of tyrosine residues on the cytoplasmic domain. These tyrosine complexes recruit signaling molecules such as the monomeric GTP-binding protein P21 ras to the membrane, where transient complexes stimulate downstream signaling to the nucleus. Increasing evidence using loss of function and gain of function in in vitro studies of neonatal myocytes implicates this signaling molecule and its downstream effector raf-1 as potential mediators of cardiac growth.34
Thyroid hormone is generally considered the classic hormonal mediator of cardiac hypertrophy. Administration of excess thyroid hormone to experimental animals produces increased heart weight that is associated with transcriptionally mediated alterations in the myosin heavy chains (MHCs), calcium-cycling proteins, and other functional constituents of the cardiomyocyte in small animals and primates.35 Thyroid hormone-induced hypertrophy appears to be an indirect effect of the T3-mediated increased oxygen consumption and resultant augmentation of cardiac work. For example, heterotopic transplantation of a nonworking rat heart into the abdominal aorta of the hyperthyroid animal is unassociated with hypertrophy, despite the presence of the transcriptionally mediated effects of the hormone in the transplanted organ and hypertrophy and typical transcriptional events in the native working heart.36,37
In addition to the indirect effects of thyroid hormone on cardiac growth, other endocrine mediators of hypertrophy have been examined. Growth hormone, which mediates its effects in large part though IGF-1, may be a mediator of physiologic hypertrophy. By contrast, there is preliminary evidence that retinoic acid and vitamin D may inhibit cardiac growth.38,39
Increases in intracellular calcium have been associated with hypertrophic cardiomyocyte growth in vitro (see Figs. 5-2 and 5-3) .40.41 por example, use of the calcium ionophore BAYK8644 enhances while application of a membrane-permeable calcium chelator inhibits the cellular hypertrophic response by affecting calcium-calmodulin-dependent protein kinase. In addition, calcineurin, a phosphatase activated by intracellular calcium, dephosphorylates nuclear factor for activation of transcription (NFAT), which translocates to the nucleus, where it activates numerous transcription factors such as GATA-4. In vitro and in vivo studies using genetically engineered mice have demonstrated that augmented levels of activity of calcineurin, NFAT, or both can initiate a hypertrophic response. However, the relative role of this pathway in normal and pathologic growth of the heart is unclear at this time.42,43
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