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CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY AND PROGRESSION TO FAILURE

The cardiac myocyte is generally considered a terminally differentiated cell that has lost its ability to divide. Under normal circumstances, functionally useful augmentation of myocyte

number (hyperplasia) cannot occur. Increased mechanical load causes an increase in the content of subcellular components and a consequent increase in cell size (hypertrophy). Increased

mechanical work owing to pressure or volume overload or trophic signals (e.g., hyperthyroidism through stimulation of beta-adrenergic receptors) increases the rate of protein synthesis,

the amount of protein in each cell, the number of sarcomeres and mitochondria, the dimension and mass of myocytes and, consequently, the size of the heart. Nevertheless, the extent to

which adult cardiac myocytes have some capacity to synthesize DNA and whether this leads to some degree of cell division is an area of considerable recent attention and debate.[15]

The extent of hypertrophy varies for different underlying causes. Heart weight usually ranges from 350 to 600 gm (up to approximately two times normal) in pulmonary hypertension and

ischemic heart disease; from 400 to 800 gm (up to two to three times normal) in systemic hypertension, aortic stenosis, mitral regurgitation, or dilated cardiomyopathy; from 600 to 1000

gm (three or more times normal) in aortic regurgitation or hypertrophic cardiomyopathy. Hearts weighing more than 1000 gm are rare.

The pattern of hypertrophy reflects the nature of the stimulus ( Fig. 12-3 ). Pressure-overloaded ventricles (e.g., in hypertension or aortic stenosis) develop pressure-overload (also called

concentric) hypertrophy of the left ventricle, with an increased wall thickness. In the left ventricle the augmented muscle may reduce the cavity diameter. In pressure overload, the

predominant deposition of sarcomeres is parallel to the long axes of cells; cross-sectional area of myocytes is expanded (but cell length is not). In contrast, volume overload stimulates

deposition of new sarcomeres and cell length (as well as

width) is increased. Thus, volume-overload hypertrophy is characterized by dilation with increased ventricular diameter. In volume overload, muscle mass and wall thickness are increased

approximately in proportion to chamber diameter. However, owing to dilation, wall thickness of a heart in which both hypertrophy and dilation have occurred is not necessarily increased,

and it may be normal or less than normal. Thus, wall thickness is by itself not an adequate measure of volume-overload hypertrophy.

Cardiac hypertrophy is also accompanied by numerous transcriptional and morphologic changes. With prolonged hemodynamic overload, gene expression is altered, leading to reexpression

of a pattern of protein synthesis analogous to that seen in fetal cardiac development; other changes are analogous to events that occur during mitosis of normally proliferating

cells ( Chapter 1 ). Early mediators of hypertrophy include the immediate-early genes (e.g., c-fos, c-myc, c-jun and EGR1). Selective up-regulation or re-expression of embryonic/fetal



forms of contractile and other proteins also occurs, including b-myosin heavy chain, ANP, and collagen (see Chapter 1 ). The increased myocyte size that occurs in cardiac hypertrophy is

usually accompanied by decreased capillary density, increased intercapillary distance, and deposition of fibrous tissue. Nevertheless, the enlarged muscle mass has increased metabolic

requirements and increased wall tension, both major determinants of the oxygen consumption of the heart. The other major factors in oxygen consumption are heart rate and contractility

(inotropic state, or force of contraction), both of which are often increased in hypertrophic states.

Thus, the geometry, structure, and composition (cells and extracellular matrix) of the hypertrophied heart are not normal. Cardiac hypertrophy constitutes a tenuous balance between

adaptive characteristics (including new sarcomeres) and potentially deleterious structural and biochemical/molecular alterations

Figure 12-3Left ventricular hypertrophy. A, Pressure hypertrophy due to left ventricular outflow obstruction. The left ventricle is on the lower right in this apical four-chamber view of the

heart. B, Altered cardiac configuration in left ventricular hypertrophy without and with dilation, viewed in transverse heart sections. Compared with a normal heart (center), the pressurehypertrophied

hearts (left and in A) have increased mass and a thick left ventricular wall, but the hypertrophied and dilated heart (right) has increased mass but a normal wall thickness.

(Reproduced by permission from Edwards WD: Cardiac anatomy and examination of cardiac specimens. In Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgesell HP (eds): Moss

and Adams Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 5th ed. Philadelphia, Williams and Wilkins, 1995, p. 86.)

Figure 12-4Schematic representation of the sequence of events in cardiac hypertrophy and its progression to heart failure, emphasizing cellular and extracellular changes.

TABLE 12-2-- Frequencies of Congenital Cardiac Malformations *

Malformation Incidence per Million Live Births %

Ventricular septal defect 4482 42

Atrial septal defect 1043 10

Pulmonary stenosis •836 •8

Patent ductus arteriosus •781 •7

Tetralogy of Fallot •577 •5

Coarctation of aorta •492 •5

Atrioventricular septal defect •396 •4

Aortic stenosis •388 •4

Transposition of great arteries •388 •4

Truncus arteriosus •136 •1

Total anomalous pulmonary venous connection •120 •1

Tricuspid atresia •118 •1

TOTAL 9757

Source: Hoffman JIE, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol 39:1890, 2002.

*Presented as upper quartile of 44 published studies. Percentages do not add to 100% owing to rounding.

echocardiography and magnetic resonance imaging). The enhanced resolving power of noninvasive methods should prove particularly useful in the study of familial structural defects,

because apparently unaffected relatives can be evaluated for subclinical evidence of anomalies.


Date: 2016-04-22; view: 726


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