Published online before print July 21, 2008, doi: 10.1161/HYPERTENSIONAHA.108.117044
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(Hypertension. 2008;52:462.)
© 2008 American Heart Association, Inc.
Editorial Commentaries |
Effects of Aldosterone on the Heart
Beyond Systemic Hemodynamics?
From the Division of Cardiovascular Sciences, Centre of Applied Medical Research, and Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain.
Correspondence to Javier Díez, Área de Ciencias Cardiovasculares, Edificio CIMA, Av Pío XII, 55, 31008 Pamplona, Spain. E-mail jadimar{at}unav.es
As predicted by Laplace’s law, the ability of the left ventricle to compensate for increasing loading conditions requires the thickening of the ventricular wall and the growth of left ventricular mass (LVM), defined as left ventricular hypertrophy (LVH) when it exceeds partition values based on distribution in normal reference populations. The presence of LVH, however, does not discriminate between a compensatory and excessive increase in LVM. Therefore, the term "inappropriate LVM" (iLVM) has been applied to conditions in which the observed level of LVM exceeds the theoretical value predicted by sex, body size, and stroke work.1 iLVM is associated with clustered geometric and functional abnormalities of the left ventricle2 and appears to be a marker of adverse cardiovascular prognosis independent of LVH.3 Recent data suggest that changes in the appropriateness of LVM from baseline to follow-up during treatment may predict a subsequent cardiovascular event in hypertensive patients.4 It has been proposed that the pathophysiological process that yields iLVM is probably linked to the protracted activity over time of humoral mediators of LV growth, such as proto-oncogenes, growth factors, hormones, and cytokines, inducing modifications that initially compensate imposed overload but eventually change the structure of myocardial tissue (eg, remodeling) and, as a consequence, impair LV function.5
The study by Muiesan et al in this issue of Hypertension6 points to aldosterone as one of the candidate hormones that may contribute to iLVM. The authors evaluated the inappropriateness of LVM in 125 patients with a diagnosis of primary aldosteronism (PA) and in 125 age-, sex-, and blood pressure–matched patients with essential hypertension. The prevalence of iLVM (defined by a ratio of observed:predicted LVM >135%) was greater in PA patients than in essential hypertension patients, irrespective of the presence or absence of traditionally defined LVH. In addition, direct correlations were observed between the ratio of observed:predicted LVM and the ratio of aldosterone:plasma renin activity levels or the postsaline infusion aldosterone concentration in PA patients. The study by Muiesan et al6 is timely, because PA is much more common than previously held, and it implies excessive organ damage to the heart, vessels, and kidney, which translates into an excess of cardiovascular events. One of the main features of the study is the careful biochemical, morphological, and hormonal methodology for the screening and confirmation of PA, as well as the adequate estimation of the appropriateness of LVM for individual cardiac load from the echocardiographic measurements. Thus, the reported findings provide compelling evidence that the chronic augmentation of aldosterone could contribute to the increase of LVM exceeding the amount needed to compensate for hemodynamic load in patients with PA.
Findings from a number of experimental studies suggest that aldosterone has the potential to directly stimulate LV growth independent of its effects on renal sodium (Na+) regulation and secondary modulation of blood pressure. For instance, transgenic mice overexpressing 11β-hydroxysteroid dehydrogenase type 2 in cardiomyocytes, which facilitates aldosterone occupancy of the mineralocorticoid receptor (MR), exhibit normal blood pressure values but spontaneously develop severe LVH.7 In addition, subcutaneous infusion of nonhypertensive doses of aldosterone to normotensive rats leads to LVH independent from blood pressure.8 Finally, also in normotensive rats, a high-salt intake for 8 weeks produces LVH associated with increased cardiac aldosterone production and aldosterone-synthase overactivity in the absence of blood pressure elevation.9
Several studies have investigated the direct hypertrophic effects of aldosterone on rat cardiac myocytes. In one study,10 aldosterone caused a 27% increase in protein incorporation and a 29% increase in myocyte surface area. This response was associated with increased mRNA levels of atrial natriuretic factor and 
- and β-myosin heavy chain, and it was suppressed by the MR antagonist spironolactone. Aldosterone stimulation acutely translocated protein kinase C- to the membrane fraction and increased the levels of phosphorylated extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinase. PD 98059, an inhibitor of the extracellular signal regulated kinase activator mitogen-activated protein kinase, and bisindolylmaleimide I, an inhibitor of protein kinase C activation, each blocked aldosterone-stimulated hypertrophy. In another study,11 aldosterone significantly increased cell size by 61% and expression of atrial natriuretic peptide by 2-fold. Na+/H+ exchanger type 1 mRNA expression and protein abundance were significantly increased, and intracellular Na+ levels were elevated. Both hypertrophy and elevated Na+ levels were prevented by the NHE-1–specific inhibitor EMD87580, as well as by spironolactone, although the increased Na+/H+ exchanger type 1 levels were prevented only by spironolactone. Finally, it has been reported that aldosterone provoked expression of hypertrophic markers (genes encoding for atrial and brain natriuretic peptides, and skeletal -actin) and phosphorylation of protein kinase D.12 Inhibition of protein kinase D abrogated the hypertrophic effects, as did spironolactone. Collectively, these data suggest that the growth response elicited by aldosterone in myocytes depends on stimulation of the MR and is associated with activation of several kinase-mediated pathways and stimulation of Na+/H+ exchanger type 1 expression and activity.
Other than hypertrophy of cardiac myocytes, aldosterone may also contribute to interstitial and perivascular fibrosis, another histomorphologic component of myocardial remodeling associated with exaggerated LV growth. In fact, chronic aldosterone infusion causes myocardial fibrosis in rat models in the setting of high-salt intake.13 The development of fibrosis is preceded by coronary and myocardial inflammation characterized by monocyte and macrophage infiltration and increased production of reactive oxygen species. The inflammatory and oxidative changes and subsequent fibrosis can be blocked by MR antagonism. Because animal models of aldosterone-stimulated cardiac fibrosis involve the systemic administration of aldosterone and salt excess, it has been difficult to dissect local fibrotic effects of aldosterone from systemic effects of Na+ retention. Nevertheless, it is to be noted that aldosterone has been shown to directly stimulate the expression of several profibrotic molecules that may contribute to the pathogenesis of cardiac fibrosis. For example, aldosterone increases the activity of transforming growth factor-β1 in cultured cardiac myocytes and its expression in cultured cardiac fibroblasts, these effects being abrogated by MR antagonists.14 In addition, aldosterone increases angiotensin II type 1 receptor mRNA expression and angiotensin II type 1 receptor binding in the heart, whereas MR antagonism decreases angiotensin II type 1 receptor mRNA and density in the heart and abrogates many of the adverse cardiac effects of aldosterone, including fibrosis.15
Thus, a relationship is emerging between aldosterone and the heart, beyond the ability of the hormone to facilitate Na+ retention and increase blood pressure, involving the activation of MR-dependent pathways in cardiac cells by the hormone (Figure). Continuing research in vitro and in vivo in animal models is required to discern a number of aspects, such as the ligand specificity of MR activation, the role for MR-dependent compared with -independent effects, and the importance of genomic compared with nongenomic pathways, as well as the potential contribution of an intracardiac synthesis of aldosterone. A general question raised by the study of Muiesan et al6 is whether the association of aldosterone with iLVM could be also translated to other conditions in which inappropriately high aldosterone concentrations coexist with increased blood pressure and exaggerated prevalence of LVH (eg, resistant hypertension and sleep apnea) or with the presence of iLVM (eg, obesity and metabolic syndrome).16 In this context, clinical trials are needed to evaluate whether MR antagonists exert a beneficial effect on LVM in patients with the above conditions and whether this effect is not only because of their ability to reduce blood pressure but also because of their ability to block the cardiac hypertrophic actions of aldosterone.
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Acknowledgments |
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Sources of Funding
This work was funded through the agreement between the Foundation for Applied Research (FIMA), and the Unión Temporal de Empresas (UTE) project Centro de Investigación Médica Aplicada (CIMA), the Red Temática de Investigación Cooperativa en Enfermedaes Cardiovasculares (RECAVA) from the Instituto de Salud Carlos III, Ministry of Health, Spain (grant RD06/0014/0008), and the Network of Excellence on Integrated Genomics, Clinical Research and Care in Hypertension (InGenious HyperCare) financed by the European Commission (contract no. LSHM-CT-2006-037093).
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. de Simone G, Devereux RB, Kimball TR, Mureddu GF, Roman MJ, Contaldo F, Daniels SR. Interaction between body size and cardiac workload influence on left ventricular mass during body growth and adulthood. Hypertension. 1998; 31: 1077–1082.
2. Chinali M, De Marco M, D'Addeo G, Benincasa M, Romano C, Galderisi M, de Simone G. Excessive increase in left ventricular mass identifies hypertensive subjects with clustered geometric and functional abnormalities. J Hypertens. 2007; 25: 1073–1078.[Medline] [Order article via Infotrieve]
3. de Simone G, Palmieri V, Koren MJ, Mensah GA, Roman MJ, Devereux RB. Prognostic implications of the compensatory nature of left ventricular mass in arterial hypertension. J Hypertens. 2001; 19: 119–125.[CrossRef][Medline] [Order article via Infotrieve]
4. Muiesan ML, Salvetti M, Paini A, Monteduro C, Galbassini G, Bonzi B, Poisa P, Belotti E, Agabiti Rosei C, Rizzoni D, Castellano M, Agabiti Rosei E. Inappropriate left ventricular mass changes during treatment adversely affects cardiovascular prognosis in hypertensive patients. Hypertension. 2007; 49: 1077–1083.
5. de Simone G, Pasanisi F, Contaldo F. Link of nonhemodynamic factors to hemodynamic determinants of left ventricular hypertrophy. Hypertension. 2001; 38: 13–18.
6. Muiesan ML, Salvetti M, Paini A, Agabiti-Rosei C, Monteduro C, Galbassini G, Belotti E, Aggiusti C, Rizzoni D, Castellano M, Agabiti-Rosei E. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension. 2008; 52: 529–534.
7. Qin W, Rudolph AE, Bond BR, Rocha R, Blomme EA, Goellner JJ, Funder JW, McMahon EG. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res. 2003; 93: 69–76.
8. Yoshida K, Kim-Mitsuyama S, Wake R, Izumiya Y, Izumi Y, Yukimura T, Ueda M, Yoshiyama M, Iwao H. Excess aldosterone under normal salt diet induces cardiac hypertrophy and infiltration via oxidative stress. Hypertens Res. 2005; 28: 447–455.[CrossRef][Medline] [Order article via Infotrieve]
9. Takeda Y, Yoneda T, Demura M, Miyamori I, Mabuchi H. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology. 2000; 141: 1901–1904.
10. Okoshi MP, Yan X, Okoshi K, Nakayama M, Schuldt AJ, O'Connell TD, Simpson PC, Lorell BH. Aldosterone directly stimulates cardiac myocyte hypertrophy. J Card Fail. 2004; 10: 511–518.[CrossRef][Medline] [Order article via Infotrieve]
11. Yamamuro M, Yoshimura M, Nakayama M, Abe K, Shono M, Suzuki S, Sakamoto T, Saito Y, Nakao K, Yasue H, Ogawa H. Direct effects of aldosterone on cardiomyocytes in the presence of normal and elevated extracellular sodium. Endocrinology. 2006; 147: 1314–1321.
12. Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004; 109: 1284–1291.
13. Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992; 120: 893–901.[Medline] [Order article via Infotrieve]
14. Chun TY, Bloem LJ, Pratt JH. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. Endocrinology. 2003; 144: 1712–1717.
15. Robert V, Heymes C, Silvestre JS, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension. 1999; 33: 981–986.
16. Shin J, Lee JU, Kim KS, Kim SG, Kim JH, Lim HK, Lee BH. Influence of abdominal circumference on the inappropriateness of left ventricular mass and diastolic function in non-obese patients. J Cardiol. 2007; 49: 323–329.[Medline] [Order article via Infotrieve]
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Hypertension 2008 52: 529-534.
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