Hormones Affecting Cardiac Function

Many hormones have direct and indirect actions on the heart ( Table 18-1 ). Hormones with cardiac actions can be synthesized and secreted by cardiomyocytes or produced by other tissues and delivered to the heart. They act on specific receptors expressed in cardiomyocytes. The great majority of these hormone receptors are plasma membrane G protein-coupled receptors (GPCRs). Non-GPCRs include the natriuretic peptide receptors, which are guanylyl cyclase-coupled receptors, and glucocorticoid/mineralocorticoid receptors, which bind androgens and aldosterone and are nuclear zinc finger transcription factors. Hormones can have activity in normal cardiac physiology or are active only in pathophysiologic conditions, or both situations can apply. Much of the understanding that has been gained over the past decade on the action of hormones in the heart has been derived from the endocrine changes associated with chronic heart failure.

Cardiac hormones are polypeptides secreted by cardiac tissues into the circulation in the normal heart. Natriuretic peptides,^{[51] [52]} aldosterone,^[53] and adrenomedullin^[54] are hormones that are secreted by cardiomyocytes. Angiotensin II, the effector hormone in the renin-angiotensin system, is also produced by cardiomyocytes.^{[55] [56]} The renin-angiotensin system is one of the most important regulators of cardiovascular physiology. It is a key modulator of cardiac growth and function. Angiotensin II stimulates two separate receptor subtypes, AT₁ and AT₂ , both of which are present in the heart. AT₁ receptors are the predominant subtype expressed in the normal adult human heart. Stimulation of AT₁ receptors induces a positive chronotropic and inotropic effect. Angiotensin II also mediates cell growth and proliferation in cardiomyocytes and fibroblasts and induces release of the growth factors aldosterone and catecholamines through stimulation of AT₁ receptors. Activation of AT₁ receptors is directly involved in the development of cardiac hypertrophy

TABLE 18-1 -- Actions of hormones on cardiac function

Hormone	Receptor	Cardiac Action	Increase with CHF
Adrenomedullin	GPCR	+Inotropy/+chronotropy	+
Aldostereone	MR	?	+
Angiotensin	GPCR	+Inotropy/+chronotropy	+
Endothelin	GPCR	?	+
Natriuretic peptides	GCCR
ANP (ANF)			+
BNP			+
Neuropeptide Y[48] [49]	GPCR	-Inotropy	+
Vasopressin	GPCR	+Inotropy/+chronotropy	+
Vasoactive intestinal peptide[50]	GPCR	+Inotropy	No
ANF, atrial natriuretic factor; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CHF, congestive heart failure; GCCR, guanylyl cyclase-coupled receptor; GPCR, G protein-coupled receptor; MR, cytosolic or nuclear mineralocorticoid receptor.

and heart failure, as well as adverse remodeling of the myocardium. In contrast, AT₂ receptor activation is counter-regulatory and is generally antiproliferative. Expression of AT₂ receptors, however, is relatively scant in the adult heart because it is most abundant in the fetal heart and declines with development. In response to injury and ischemia, AT₂ receptors become upregulated. The precise role of AT₂ receptors in the heart remains to be defined.

The beneficial effects of blockade of the renin-angiotensin system by using angiotensin-converting enzyme inhibitors in the treatment of heart failure have been attributed to inhibition of AT₁ receptor activity. In addition to the renin-angiotensin system, other cardiac hormones that have been shown to play pathogenic roles in the promotion of cardiomyocyte growth and cardiac fibrosis, the development of cardiac hypertrophy, and the progression of congestive heart failure include aldosterone,^[53] adrenomedullin,^{[57] [58] [59]} natriuretic peptides,^{[51] [52]} angiotensin,^{[60] [61]} endothelin,^[62] and vasopressin.^{[63] [64]}

Increased stretch of the myocardium stimulates the release of atrial natriuretic protein (ANP) and B-type natriuretic protein (BNP) from the atria and ventricles, respectively. Both ANP and BNP bind to natriuretic peptide receptors to generate the second messenger cyclic guanosine monophosphate and represent part of the cardiac endocrine response to hemodynamic changes caused by pressure or volume overload. They also participate in cardiac organogenesis of the embryo heart and cardiovascular system.^{[51] [52]} In patients with chronic heart failure, elevation of serum ANP and BNP levels has been documented to be a predictor of mortality.

Adrenomedullin is a recently discovered cardiac hormone that was originally isolated from pheochromocytoma tissues. Adrenomedullin increases accumulation of cAMP and has direct positive chronotropic and inotropic effects.^{[54] [57] [58]} Adrenomedullin, with interspecies and regional variations, has also been shown to increase nitric oxide production and functions as a potent vasodilator.

Aldosterone is one of the cardiac-generated steroids, although its physiologic significance remains to be defined. It binds to mineralocorticoid receptors and can increase the expression or activity (or both) of cardiac

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