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Chapter 4: PRINCIPLES OF MOLECULAR CARDIOLOGY THE CARDIAC GROWTH RESPONSE

The growth response of the myocardium to injury, whether it be myocardial infarction, hypertension, or valvular disease, is a major determinant of morbidity and mortality. Growth is the major long-term adaptive mechanism of the heart (see Chap. 5). In hypertrophy, the sarcomeres are added in parallel, which gives rise to thickened walls of the cardiac chambers.53 In contrast, in cardiac dilatation, the growth is achieved by adding sarcomeres in sequence.54 It remains to be determined whether dilated cardiomyopathy occurring as a pathologic entity is a normal compensatory response or represents abnormal growth or an inadequate growth response.

Developmental growth in utero or during prepuberty and puberty is associated with orchestrated stimuli from a variety of hormones such as growth hormone. This is in sharp contrast to the restricted cardiac growth observed in the adult in response to injury. For example, in aortic constriction, the left ventricle responds with increased mass, while the right ventricle is not affected. Hammond et al.55 in 1979 demonstrated that the growth stimulus was indeed localized to the affected organ. Left ventricular hypertrophy was induced by aortic coarctation in the dog. Supernatants of the homogenized, hypertrophied left ventricle from dogs with aortic coarctation and normal dogs were used to perfuse a normal canine heart. Messenger RNA of the perfused heart was increased by extracts from the hypertrophied left ventricle but not from the normal myocardium, indicating the presence of a growth factor in the hypertrophied ventricle. This established the presence of a localized cellular stimulus acting through autocrine, paracrine, or intracrine mechanisms to induce cardiac hypertrophy. This was confirmed by Imamura et al.56 in 1990; they showed that hypertrophy occurs in the left ventricle in response to aortic coarctation without growth in other chambers of the heart, while banding the pulmonary artery induced hypertrophy of the right ventricle without involvement of the left ventricle. Similarly, hypertrophy induced by volume overload, myocardial infarction,57 or other forms of injury is restricted to the cardiac chamber involved. Despite the myocyte not increasing in number in the adult heart during hypertrophy, certain other features are interesting and unique. Cardiac myocytes, during their normal growth response, exhibit DNA synthesis (multiple nuclei)58 and the reexpression of several fetal proteins otherwise expressed only in embryonic cells.59 The rational basis for the reexpression of fetal protein is not obvious. The response has been referred to as adaptive, maladaptive, or part of a triggered program response.28 The atrial natriuretic factor gene is expressed in the atria and ventricles in the embryonic state but not in the normal adult ventricle. It is reexpressed in the ventricle during hypertrophy.60 Calcium ATPase, an enzyme essential to cardiac contractility, is decreased in the hypertrophied human ventricle.61 It is well documented in the developing mammalian heart in utero that the initial actin gene expressed is that of smooth muscle type, followed by that of skeletal muscle and finally cardiac muscle.62 The functional significance, if any, of the reexpression of fetal genes when the cardiac growth program is turned on in the adult heart is unknown. It is possible that the growth response can only be activated through expression of a family of genes. The master gene controlling expression of such a family could be triggered by a growth factor stimulated by pressure overload; this could result in a cascade of genes expressed, most of which are incidental rather than adaptive or maladaptive. For example, in skeletal muscle there is a master gene, myo-D,63 that triggers the differentiation of skeletal muscle. When this occurs, a cascade of genes is downregulated, and another cascade of genes is upregulated. Myo-D is not expressed in cardiac muscle, and no such triggering factor has been found for cardiac myocyte differentiation (see Chap. 9).

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