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Cardiac Aldosterone Synthesis?

Published:February 24, 2006DOI:https://doi.org/10.1016/j.amjcard.2006.01.005
      Recognition that a variety of hormones affect the heart and blood vessels dates back well over a century, and about 25 years ago, it was firmly established that the heart is also an endocrine organ. This era began with de Bold’s
      • de Bold A.J.
      Heart atrial granularity effects of changes in water-electrolyte balance.
      discovery that the quantity of electron-dense “atrial specific granules” previously described by Jamieson and Palade
      • Jamieson J.D.
      • Palade G.E.
      Specific granules in atrial muscle cells.
      varied with maneuvers that altered intravascular volume status. By 1982, it was recognized that these granules contained and released a potent peptide called atrial natriuretic peptide.
      • Flynn T.G.
      • de Bold M.L.
      • de Bold A.J.
      The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties.
      (Palade
      • Palade G.E.
      Secretory granules in the atrial myocardium.
      had previously hypothesized they might contain catecholamines.) The discovery that a related peptide, B-type natriuretic peptide, was synthesized and released by cardiac ventricles, especially when diseased, soon followed. The next series of hormone to be localized within the heart and vascular tissues was the renin-angiotensin system (RAS). The original description of the circulating RAS identified the liver as the major source of angiotensinogen, the renal juxtaglomerular apparatus as the major site of renin generation, and pulmonary vascular endothelium as the major source of angiotensin-converting enzyme, which catalyzes the conversion of angiotensin I to angiotensin II. By the 1980s, it was clear that most, or all, of these RAS components could also be synthesized in a variety of other locations, including the cardiovascular system.
      • Dzau V.J.
      • Re R.
      Evidence for the existence of renin in the heart.
      • Dostal D.E.
      • Baker K.M.
      The cardiac renin-angiotensin system conceptual, or a regulator of cardiac function?.
      Angiotensin II (and perhaps other peptides) was shown to have important autocrine and paracrine actions that affected cardiac and vascular cell growth, remodeling, inflammation, apoptosis, and so forth. Thus, the beneficial action of drugs, which disrupts this hormone cascade, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, in a variety of pathologic conditions was shown to have systemic (circulating RAS) and local (tissue RAS) components.
      Does this brief list of cardiac endocrine synthetic function complete the heart’s hormonal repertoire? Undoubtedly the answer to that question is no! The report by Wasywich et al in the current issue of the Journal suggests that the heart can also synthesize aldosterone.
      • Wasywich C.A.
      • Webster M.W.I.
      • Richard A.M.
      • Stewart R.A.H.
      Coronary sinus and ascending aortic levels of aldosterone, angiotensin II, and B-type natriuretic peptide in patients with aortic stenosis and in patients with coronary heart disease.
      All the hormones the heart is known to synthesize are peptides. Can the heart and/or vascular tissue also manufacture this, and perhaps other, steroid hormones? Investigators have sought evidence for such synthesis for >10 years. The remarkable results of the Randomized Aldactone Evaluation Study increased the enthusiasm of investigators to search for this possibility. In patients with moderate to severe heart failure, spironolactone produced a 30% improvement in survival compared with standard therapy.
      • Pitt B.
      • Zannad F.
      • Cody R.
      • Castaigne A.P.A.
      • Palensky J.
      • Wittes J.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
      This dramatic benefit cannot be entirely attributed to the drug’s modest diuretic effect but rather is believed to be due to the blockade of aldosterone’s cardiovascular remodeling and fibrosing effects. Is this effect entirely the result of blocking systemic aldosterone activity? Is it possible that aldosterone is also synthesized within the heart and that spironolactone blocks local (autocrine or paracrine) effects? This is an enticing idea and an exciting area of research, but so far, the evidence that this actually occurs is very weak. The molecular machinery to manufacture aldosterone (i.e., the messenger ribonucleic acid to direct the synthesis of the requisite series of enzymes) has been identified in the heart and vascular tissues of some species (rat) but not others (mouse).
      • Gomez-Sanchez C.E.
      • Gomez-Sanchez E.P.
      • Montgomery G.V.
      Editorial cardiac steroidogenesis—new sites of synthesis, or much ado about nothing?.
      • Funder J.W.
      Cardiac synthesis of aldosterone going, going, gone … ?.
      Young et al
      • Young M.J.
      • Clyne C.D.
      • Cole T.J.
      • Funder J.W.
      Cardiac steroidogenesis in normal and failing heart.
      could not identify the required message in the normal human heart but did show low levels of aldosterone synthase messenger ribonucleic acid in the hearts of patients with congestive failure. However, even if one accepts that very low levels of these enzymes do occur in the human heart (and this remains controversial), it would not prove that clinically significant quantities of aldosterone are locally synthesized. Is adequate substrate available, and is the Michelis’ Constant (K max) of these enzymes low enough to drive the synthetic process?
      A more direct, although less biochemically elegant, approach is that taken by Wasywich et al
      • Wasywich C.A.
      • Webster M.W.I.
      • Richard A.M.
      • Stewart R.A.H.
      Coronary sinus and ascending aortic levels of aldosterone, angiotensin II, and B-type natriuretic peptide in patients with aortic stenosis and in patients with coronary heart disease.
      in this issue. They ask whether the human heart can synthesize enough aldosterone to generate a concentration step-up from the systemic circulation (aortic root) to blood in the coronary sinus. They evaluated 19 patients with severe aortic stenosis and 18 with stable ischemic heart disease and report that the aldosterone concentration in the coronary sinus was 20% greater than that in aortic blood. As they point out, previous studies of this question have generated conflicting results. Some investigators found similar increments in patients with cardiac pathology and no gradient in those with normal hearts.
      • Mizuno Y.
      • Yoshimura M.
      • Yasue H.
      • Sakamoto T.
      • Ogawa H.
      • Kugiyama K.
      • Harada E.
      • Nakayama M.
      • Nakamura S.
      • Ito T.
      • et al.
      Aldosterone production is activated in failing ventricle in humans.
      • Mizuno Y.
      • Yasue H.
      • Yoshimura M.
      • Fujii H.
      • Yamamoto N.
      • Nakayama M.
      • Harada E.
      • Sakamoto T.
      • Nakamura S.
      • Ito T.
      • et al.
      Effects of perindopril on aldosterone production in the failing human heart.
      However, others reported no gradient at all
      • Funder J.W.
      Cardiac synthesis of aldosterone going, going, gone … ?.
      or a negative gradient, that is, the cardiac extraction of aldosterone.
      • Tsutamoto T.
      • Wada A.
      • Maeda K.
      • Mabuchi N.
      • Hayashi M.
      • Tsutsui T.
      • Ohnishi M.
      • Sawaki M.
      • Fujii M.
      • Matsumoto T.
      • et al.
      Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure.
      Even if the present results are confirmed, it does not prove that the heart is the locus of synthesis. The heart and other tissues may extract and store aldosterone or aldosterone metabolites and then release the stored hormone in response to various stimuli, such as a cardiac catheterization. So the jury is still out on whether the heart is a steroid hormone-synthesizing organ. I continue to keep an open mind about this possibility, but I think the odds are <50 to 50.

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