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The Cardiomyopathy of Overload: An Unnatural Growth Response in the Hypertrophied Heart

Arnold M. Katz
[+] Article and Author Information

From the University of Connecticut School of Medicine, Farmington, Connecticut. Requests for Reprints: Arnold M. Katz, MD, Cardiology Division, University of Connecticut Health Center, Farmington, CT 06030-1305. Acknowledgments: The author thanks the Class of 1996 of the University of Connecticut Schools of Medicine and Dental Medicine for their interest in and enthusiasm for his lectures on this topic, which led to the preparation of this article; and James B. Young, MD, who pointed out the contribution of Austin Flint to our understanding of the importance of cardiac hypertrophy. Grant Support: In part by Program Project HL-33026 from the National Heart, Lung, and Blood Institute.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;121(5):363-371. doi:10.7326/0003-4819-121-5-199409010-00009
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Heart failure is a progressive condition with a 5-year survival of less than 50%. This poor prognosis, which can be reproduced by overloading the hearts of experimental animals, may reflect molecular abnormalities caused when overload stimulates adult cardiac myocytes to undergo hypertrophy. Because these terminally differentiated cells have little or no capacity to divide, hypertrophy represents an unnatural growth response; however, the mechanism by which overload shortens survival remains speculative. Modification of this unnatural growth response by converting enzyme inhibitors and nitrates, which have growth inhibitory as well as vasodilator effects, may contribute to the ability of these drugs to improve prognosis in patients with heart failure.

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Figure 1.
Converting enzyme inhibitors decrease the formation of angiotensin II and the breakdown of bradykinin.II323322

Decreased levels of angiotensin II (A ), by blunting the cascade shown at the left of the figure, inhibit the production of two intracellular messengers: inositol 1,4,5-trisphosphate (InsP ) and diacylglycerol (DAG). Because the former releases calcium (Ca +) from internal stores, decreased InsP production in smooth muscle cells has a vasodilator effect. Inhibition of the cascade initiated by angiotensin II also decreases the production of the mitogen DAG, so that converting enzyme inhibitors can inhibit cell growth. Inhibition of bradykinin breakdown has even more complex effects, shown at the right of the figure. Increased bradykinin levels lead to the production of InsP and DAG. However, because the net effect of increased bradykinin is vasodilation, the calcium released by the bradykinin cascade appears to favor the production of several vasodilator molecules; these include nitric oxide (produced when an increase in cytosolic calcium activates nitric oxide synthase) and the eicosanoids, prostaglandin E and prostacyclin (released when calcium activates the lipolytic enzyme phospholipase A [PLA]). Bradykinin also activates adenylyl cyclase, which increases the production of yet another vasodilator molecule, cyclic adenosine monophosphate (cAMP). The nitric oxide formed by the bradykinin cascade appears also to have important growth-inhibitory effects. Together, these effects account for the ability of the converting enzyme inhibitors to unload the heart by decreasing peripheral resistance (afterload), and to exert growth-inhibitory effects. The latter, by slowing the progression of maladaptive hypertrophy, may play a role in the ability of the converting enzyme inhibitors to prolong survival in patients with heart failure. G protein = guanine nucleotide-binding coupling proteins; PKC = protein kinase C; and PLC = phospholipase C.

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Figure 2.
Overall growth patterns in the proliferating myocytes of the embryonic heart, the terminally differentiated myocytes of the normal adult heart, and the maladaptively hypertrophied myocytes of the failing heart.Left.Right.

In the embryonic heart, growth factors stimulate synthesis of fetal-specific gene products that, because protein synthesis is matched to active cell cycling, lead to normal cell division. Center. Withdrawal of growth factors and binding of myogenic factors to the E box in the terminally differentiated cells of the normal adult heart slows protein synthesis, inhibits the cell cycle, and favors the synthesis of adult muscle-specific gene products. Overloading of the adult heart initiates an immediate-early gene response that reactivates growth factor stimulation; this, in turn, accelerates protein synthesis and favors the expression of fetal muscle-specific gene products. However, because the cell cycle remains blocked, the overloaded heart undergoes an unnatural growth response. One consequence of this response is accelerated myocardial cell death, which may be partly caused by the ability of some of the activated growth factors not only to stimulate protein synthesis but also to cause programmed cell death (apoptosis).

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