Title: Will the Lessons From Primary Aldosteronism Change the Treatment of Hypertension and Left Ventricular Hypertrophy?
Abstract: HomeHypertensionVol. 50, No. 5Will the Lessons From Primary Aldosteronism Change the Treatment of Hypertension and Left Ventricular Hypertrophy? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWill the Lessons From Primary Aldosteronism Change the Treatment of Hypertension and Left Ventricular Hypertrophy? Richard J. Auchus and Mark H. Drazner Richard J. AuchusRichard J. Auchus From the Divisions of Endocrinology and Metabolism (R.J.A.) and Cardiology (M.H.D.), Department of Internal Medicine, and the Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas. and Mark H. DraznerMark H. Drazner From the Divisions of Endocrinology and Metabolism (R.J.A.) and Cardiology (M.H.D.), Department of Internal Medicine, and the Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas. Originally published1 Oct 2007https://doi.org/10.1161/HYPERTENSIONAHA.107.097303Hypertension. 2007;50:837–839Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 1, 2007: Previous Version 1 The renin-angiotensin-aldosterone system effectively defends against volume depletion, but in most developed nations, dietary sodium is high, and aldosterone production should be suppressed. The syndrome of primary aldosteronism demonstrates the consequences of autonomous aldosterone production in a sodium-replete society. For many years, primary aldosteronism was thought to be an esoteric disorder only diagnosed by academicians at a handful of institutions worldwide. Conn, Biglieri, Bravo, and others characterized the syndrome and developed diagnostic strategies circa 1960–1980. Most clinicians, however, could not execute these algorithms, and management was unsatisfactory because of poor methods for localizing aldosterone production and limited options for medical management. Interest shifted to other mechanisms of hypertension, but during the last 20 years, the advent of commercial assays for renin and aldosterone, the broader use of adrenal vein sampling, and the development of selective aldosterone antagonists have rejuvenated interest in primary aldosteronism.1 Furthermore, end-organ damage is more severe in primary aldosteronism than in essential hypertension, and considerable evidence implicates the activation of mineralocorticoid receptors in these tissues as the mechanism.Implicit in this aldosterone renaissance is the importance of making the diagnosis of primary aldosteronism to allow implementation of tailored therapy. Proteinuria is more prevalent in patients with primary aldosteronism than in those with essential hypertension,2 and the excess proteinuria largely reverses after treatment with surgery or spironolactone.3 Thus, the benefits reaped from the detection of primary aldosteronism and the implementation of targeted therapy extend beyond optimal control of blood pressure.Another malady associated with primary aldosteronism is left ventricular (LV) hypertrophy (LVH).4 LVH is associated with adverse cardiovascular events and all-cause mortality.5 Therapy, which leads to regression of LVH in hypertensive subjects, reduces these risks.6 Despite the importance of LVH as a risk factor and the high prevalence of LVH in primary aldosteronism, the influence of targeted therapy on LVH in this disorder was unknown until now.In this issue of Hypertension, the group in Udine presents the results of their long-term follow-up of a cohort of hypertensive subjects, including groups with aldosterone-producing adenomas treated with adrenalectomy, idiopathic hyperaldosteronism treated with spironolactone, and essential hypertension treated with drugs other than spironolactone. With a mean follow-up of 6.4 years, systolic blood pressure declined 30 mm Hg in spironolactone-treated patients and 33 mm Hg in adrenalectomized patients. In concert with this reduction in blood pressure, the prevalence of LVH decreased from 38% to 8% among those adrenalectomized and from 30% to 7% among those treated with spironolactone (P<0.05 for both). In these groups, LV mass indexed to height2.7 fell 15% to 20%, from 52.8 to 42.8 g/m2.7 in adrenalectomized patients, and from 51.6 to 43.9 g/m2.7 in spironolactone-treated patients.7The data presented by Catena et al7 raise several important questions regarding the treatment of primary aldosteronism, as well as the management of hypertension in general. First, in primary aldosteronism, is adrenalectomy equivalent to aldosterone antagonist therapy? In the present study, mean blood pressure declined comparably in the 2 groups at the end of follow-up, within 2 mm Hg. A significant reduction in LV mass was seen with adrenalectomy but not spironolactone after 1 year, but the indexed LV mass at the end of follow-up was only slightly higher in the spironolactone arm, and we are not told whether this difference was statistically significant. Furthermore, it is not known whether these slight differences in blood pressure and LV mass reduction translate into improved clinical outcomes. It is also important to recognize that direct comparison of the adrenalectomized and pharmacologically treated patients may not be justified, because individuals with aldosterone-producing adenomas chosen for adrenalectomy appeared to show greater aldosterone excess than those with idiopathic hyperaldosteronism, as typically observed.1,8 Spironolactone effectively treats the hypertension and hypokalemia of aldosterone-producing adenomas,1 but whether spironolactone would have been equally efficacious in reducing LVH among those with a demonstrated adenoma is uncertain.The second question concerns the criteria used to diagnose primary aldosteronism. Catena et al7 relied on a single serum aldosterone measurement after saline infusion and did not routinely use adrenal vein sampling for localization.1,8 The aldosterone cutoff of 50 pg/mL (5 ng/dL or 140 pmol/L) after saline infusion is the most generous of several criteria used to diagnose primary aldosteronism1 and demonstrates the fine line between low-renin hypertension and primary aldosteronism not caused by tumors. Among patients with primary aldosteronism, is the benefit proportionate to the severity of the disease, or do those with an aldosterone of 50 pg/mL after saline benefit as much from targeted therapy as those with an aldosterone of 500 pg/mL?The third question raised by this study is how much of the benefit of LV mass reduction derived from effects on blood pressure reduction versus antagonism of mineralocorticoid receptors in the heart? The authors attempt to dissect these 2 effects, including a comparison of LV mass changes in individuals with primary aldosteronism after targeted therapy (adrenalectomy or spironolactone) with the reduction of LV mass in a comparator group of individuals with essential hypertension who experienced a similar reduction in systolic blood pressure (30 mm Hg) during treatment with agents other than spironolactone. The LV mass reduction was greater in the primary aldosteronism group than the essential hypertension group. However, there are important caveats to this analysis, including potential bias, given that only 108 of 274 subjects with essential hypertension had paired echocardiographic data reported. Further complicating this issue is that, in the subjects with primary aldosteronism, the reduction in LV mass was significantly related to the reduction in blood pressure in multivariable analysis. Was the LV mass regression of 32 g (spironolactone) and 44 g (adrenalectomy) observed after a mean of 6.4 years by Cateno et al7 greater than would be expected for the 30- to 33-mm Hg reduction in blood pressure achieved in this study? In comparison, the Losartan Intervention for Endpoint Reduction Study achieved a 28-mm Hg reduction in systolic blood pressure over 5 years with losartan and other drugs, and this therapy led to a 47-g reduction in LV mass.6 Overall, it is difficult if not impossible to cleanly dissociate the relative contributions of blood pressure lowering and direct effects of cardiac mineralocorticoid receptor blockade on LV mass regression in the study by Cateno et al.7The fourth important question raised by Catena et al7 is what role aldosterone antagonism should play in the treatment of hypertension among the broad population of patients with essential hypertension who would have lower values of serum aldosterone after saline infusion (eg, 20 to 40 pg/mL). In resistant hypertension, spironolactone therapy often provides impressive systolic blood pressure reductions of >20 mm Hg.9 The prevalence of primary aldosteronism in patients with resistant hypertension is ≈20%,10 yet spironolactone nicely lowers blood pressure in this subgroup, whether individual patients meet the strict criteria for primary aldosteronism or not.11 Perhaps this distinction also matters little in promoting the regression of LV mass. Therapy with eplerenone has been shown to regress LVH beyond that achieved with converting-enzyme inhibitor therapy alone in patients with essential hypertension.12There is little argument that surgical management of an aldosterone-producing adenoma is a beneficial and gratifying treatment approach, particularly for young patients with severe disease8 in whom the adverse effects of spironolactone are most bothersome.1 The debates concerning primary aldosteronism center on the populations who should be screened, the pathogenesis and optimal management of idiopathic hyperaldosteronism, and the distinction of low-renin hypertension from aldosterone excess. Do all patients with hypertension and evidence of end-organ damage benefit from aldosterone antagonist therapy? If so, why do they benefit if aldosterone is low? What would be the result of a study that randomly assigned patients with aldosterone-producing adenomas, idiopathic hyperaldosteronism, and essential hypertension to spironolactone versus other antihypertensives? How will these treatments influence clinical outcomes, including myocardial infarction, stroke, and overall survival in patients with various forms of hypertension?Already, aldosterone antagonism is an accepted therapy for patients with heart failure and LV systolic dysfunction.13 The data from Cateno et al7 strongly support the continued use of therapy targeted against aldosterone excess among those with primary aldosteronism. Their data also highlight the need for additional investigation into whether aldosterone antagonism should be more broadly adopted in essential hypertension, particularly in those patients with LVH. We suspect that aldosterone antagonists will benefit others with hypertensive cardiac hypertrophy given their efficacy in resistant hypertension,9,11 even if direct effects from antagonism of mineralocorticoid receptors in the heart are not a major mechanism. Furthermore, until these data are available, it is prudent to normalize the blood pressure in patients with hypertension and LVH by any means possible.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingR.J.A. is supported by a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund (1005954). R.J.A. and M.H.D. are supported by the Donald W. Reynolds Cardiovascular Clinical Research Center at UT Southwestern.DisclosuresNone.FootnotesCorrespondence to Richard J. Auchus, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8857. E-mail [email protected] References 1 Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf). 2007; 66: 607–618.CrossrefMedlineGoogle Scholar2 Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mannelli M, Matterello MJ, Montemurro D, Palumbo G, Rizzoni D, Rossi E, Pessina AC, Mantero F, Participants PS. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension. 2006; 48: 232–238.LinkGoogle Scholar3 Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Catena C. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006; 295: 2638–2645.CrossrefMedlineGoogle Scholar4 Matsumura K, Fujii K, Oniki H, Oka M, Iida M. Role of aldosterone in left ventricular hypertrophy in hypertension. Am J Hypertens. 2006; 19: 13–18.CrossrefMedlineGoogle Scholar5 Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566.CrossrefMedlineGoogle Scholar6 Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris K, Aurup P, Dahlöf B. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA. 2004; 292: 2350–2356.CrossrefMedlineGoogle Scholar7 Catena C, Colussi GL, Lapenna R, Nadalini E, Chiuch A, Gianfanga P, Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension. 2007; 50: 911–918.LinkGoogle Scholar8 Nwariaku FE, Miller BS, Auchus RJ, Holt S, Watumull L, Dolmatch B, Nesbitt S, Vongpatanasin W, Victor R, Wians FH Jr, Livingston E, Snyder WH III. Primary hyperaldosteronism: advantages of adrenal vein sampling for subtype differentiation. Arch Surg. 2006; 141: 497–503.CrossrefMedlineGoogle Scholar9 Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR; on behalf of the Anglo-Scandinavian Cardiac Outcomes Trial Investigation. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007; 49: 839–845.LinkGoogle Scholar10 Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002; 40: 892–896.LinkGoogle Scholar11 Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003; 16: 925–930.CrossrefMedlineGoogle Scholar12 Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003; 108: 1831–1838.LinkGoogle Scholar13 Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByUeda T, Tsurutani Y, Osada J, Inoue K, Hoshino Y, Ono M, Nakai K, Saito J, Yumoto K and Nishikawa T (2022) Comparison of Echocardiographic Changes Between Surgery and Medication Treatment in Patients With Primary Aldosteronism, Journal of the American Heart Association, 11:13, Online publication date: 5-Jul-2022. November 2007Vol 50, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.107.097303PMID: 17909118 Originally publishedOctober 1, 2007 PDF download Advertisement SubjectsHypertrophyMyocardial Biology