For many decades, aldosterone has been seen as a hormone

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1 Mineralocorticoids Long-Term Cardiac Effects of Adrenalectomy or Mineralocorticoid Antagonists in Patients With Primary Aldosteronism Cristiana Catena, GianLuca Colussi, Roberta Lapenna, Elisa Nadalini, Alessandra Chiuch, Pasquale Gianfagna, Leonardo A. Sechi Abstract Exposure to excess aldosterone results in cardiac damage in hypertensive states. We evaluated the long-term cardiac structural and functional evolution in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with primary aldosteronism were enrolled in a prospective study and were followed for a mean of 6.4 years after treatment with adrenalectomy (n 24) or spironolactone (n 30). At baseline, echocardiographic measurements of patients with primary aldosteronism were compared with those of 274 patients with essential hypertension. Patients with primary aldosteronism had greater left ventricular mass, more prevalent left ventricular hypertrophy, lower early:late-wave diastolic filling velocities ratio, and longer deceleration time than patients with essential hypertension but no differences in relative wall thickness and systolic function. During follow-up, average blood pressure was 135/82 and 137/82 mm Hg in patients treated with adrenalectomy and spironolactone, respectively. In the initial 1-year period, left ventricular mass decreased significantly only in adrenalectomized patients. Subsequent changes in left ventricular mass were greater in patients treated with spironolactone, with an overall change from baseline to the end of follow-up that was comparable in the 2 groups. Prevalence of hypertrophy decreased in both treatment groups, whereas diastolic parameters had only mild and nonsignificant improvement. Changes in blood pressure and pretreatment plasma aldosterone were independent predictors of left ventricular mass decrease in both treatment groups. Thus, in the long-term, both adrenalectomy and spironolactone are effective in reducing left ventricular mass in patients with primary aldosteronism, with effects that are partially independent of blood pressure changes. (Hypertension. 2007;50: ) Key Words: adrenalectomy echocardiography left ventricular hypertrophy spironolactone diastolic filling For many decades, aldosterone has been seen as a hormone almost exclusively involved in the regulation of body fluids, maintenance of electrolyte balance, and blood pressure homeostasis. 1 More recent views, however, indicate that aldosterone can contribute to cardiac damage independent of blood pressure. 2 In animal studies, exposure to excess aldosterone levels has been associated with collagen deposition, myocardial fibrosis, and ventricular remodeling, 3 and 2 large clinical trials have reported a significant decrease in the mortality rate of patients with heart failure who were treated with aldosterone antagonists. 4,5 Primary aldosteronism is a disease associated with hypertension that offers an important clinical opportunity for assessing the effects of excess aldosterone on the cardiovascular system because, in this condition, its effects are isolated from those of the renin-angiotensin axis. The widespread use of the aldosterone:renin ratio as a screening test has led to more efficient identification of this endocrine disorder. 6,7 Cardiac structural and functional changes are common consequences of hypertensive states and have been demonstrated also in patients with primary aldosteronism, along with some additional surrogate cardiovascular end points (reviewed in Reference 2). Many cross-sectional echocardiographic evaluations and a few short-term follow-up studies have reported variable results, 8 20 with excess left ventricular (LV) hypertrophy and diastolic dysfunction being the most common, 8 15 although not uniformly detected, abnormalities. We have further explored the relationship between aldosterone and the heart by assessing, in the long term, cardiac anatomic and functional evolution of patients with primary aldosteronism after treatment with adrenalectomy or aldosterone antagonists. Methods Patients Fifty-four consecutive patients with primary aldosteronism were included in a prospective study. Recruitment of patients, diagnostic Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received May 28, 2007; first decision June 25, 2007; revision accepted September 4, From the Division of Internal Medicine, Hypertension and Cardiovascular Unit (C.C., G.C., R.L., E.N., A.C., L.A.S.), and Division of Cardiology (P.G.), Department of Experimental and Clinical Pathology and Medicine, University of Udine, Udine, Italy. Correspondence to Leonardo A. Sechi, Clinica Medica, Università di Udine, Department of Experimental and Clinical Pathology and Medicine, Piazzale S. Maria della Misericordia, 1, Udine, Italy. sechi@uniud.it 2007 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 912 Hypertension November 2007 criteria, and follow-up have been described in detail in previous publications. 21,22 Patients were referred to the hypertension clinic of our university for evaluation of their hypertensive state: 36 patients had persistent hypokalemia, and 27 had hypertension resistant to a triple-drug regimen. Blood pressure was measured by sphygmomanometry, and hypertension was diagnosed according to established guidelines. 23 All of the patients seen at the clinic are screened with extensive testing to define the cause of hypertension. Seven percent of patients with primary aldosteronism were taking no antihypertensive drug, 9% were on monotherapy, and the remaining 84% had multiple-drug treatment with an average of 2.9 drugs per patient. Patients treated with antihypertensive drugs were withdrawn from treatment a minimum of 2 weeks before diagnostic assessment. -Blockers, lipophilic calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers were withdrawn for 3 weeks. No patient was taking mineralocorticoid receptor antagonists before the study. Primary aldosteronism was screened by the demonstration of an increased plasma aldosterone:active renin ratio ( 20) 21,24 in the presence of a plasma aldosterone of 150 pg/ml, and the diagnosis was confirmed by the lack of aldosterone suppression (values of 50 pg/ml) after an intravenous saline load (2 L of 0.9% saline infused over 4 hours). 25 This test has been shown to be highly effective in the distinction of both tumoral and idiopathic aldosteronism from low-renin essential hypertension. 26 Measurements were performed under a normal sodium diet, and 24-hour urinary sodium excretion was checked in all of the patients. Plasma potassium concentration of 3.5 mmol/l was corrected by oral supplementation before the assessment of the plasma aldosterone:active renin ratio and saline suppression test. Differentiation between adrenal adenoma and idiopathic aldosteronism was obtained by high-resolution computed tomography scan, followed by selective adrenal vein sampling (n 14) and/or adrenal scintigraphy with iodocholesterol (n 47), which was performed under dexamethasone suppression. In patients who underwent adrenal vein sampling, adrenal vein cannulation was considered successful if the adrenal vein/inferior vena cava cortisol gradient was 2, and lateralization was defined by measurement of an aldosterone:cortisol ratio in 1 adrenal vein that was 4 times the ratio in the other adrenal vein. 7 In all of the patients who underwent adrenalectomy, adenoma was confirmed by histology and normalization of plasma aldosterone concentrations. Primary aldosteronism was treated by either unilateral adrenalectomy or spironolactone (range: 50 to 300 mg/d; average dose: 121 mg/d), and treatment was followed by normalization of blood pressure or significant improvement of hypertension in all of the patients. A total of 274 patients with essential hypertension served as control subjects for baseline comparisons. These patients were recruited at our hypertension clinic and were selected by frequency matching after specification of inclusion criteria to avoid age, gender, body mass index, and estimated duration of hypertension as potential confounding variables. In these patients, secondary causes of hypertension were excluded after an appropriate drug washout. Among patients with essential hypertension, 11% were taking no antihypertensive drug, 16% were on monotherapy, and 73% had multiple-drug treatment with a mean of 2.3 antihypertensive agents per patient. Informed consent was obtained from all of the patients, and the protocol was approved by the local ethics committee. Echocardiographic Examination Echocardiography was performed by the same investigators who were unaware of patient diagnosis. 27 Measurements of LV internal dimensions and wall thickness were obtained with commercial machines (Sonos HP1000, Hewlett-Packard or Aplio CV, Toshiba Medical Systems) and a 2.5-MHz transducer under bidimensional cross-sectional control, with the patients in the partial left decubitus position. The LV geometric pattern was defined by the ratio of the posterior LV wall thickness to one half of the LV internal dimension, and a value of 0.44 was used to define LV concentric geometry. 28 The LV mass index (LVMI) was calculated by the Penn Convention formula 29 and adjusted for body height with a cutoff value of 51 g/m 2.7 that was used to define LV hypertrophy in both sexes. 30 Systolic function was estimated by the ejection fraction and both endocardial and midwall fractional shortening (FS), with the latter taking into account epicardial migration of the midwall during systole. 31 Endocardial FS was expressed as a percentage of the value predicted in normal subjects for meridional end-systolic stress. 32 Circumferential end-systolic stress was calculated at the midwall, 33 and the equation of de Simone et al 34 was used to predict expected midwall shortening. The observed:predicted midwall shortening ratio was used as an index of LV systolic performance. 35 Pulsed Doppler recordings at the level of the mitral valve tips were obtained from apical 4-chamber scans to measure early and late-wave diastolic filling velocities, their ratio (E/A ratio), and the early wave deceleration time. 36 Follow-Up All 54 of the patients with primary aldosteronism were prospectively followed up. 21 Twenty four of 29 patients with adrenal adenoma underwent adrenalectomy; among the remaining 5 patients, 2 had bilateral adenoma, and 3 refused surgery and were treated with spironolactone. Treatment with spironolactone was started with a dose of 100 mg/d that was titrated to reach the target blood pressure. Clinical assessment and laboratory tests were repeated 1, 3, and 6 months after enrollment and every 12 months thereafter. At each visit, antihypertensive therapy was adjusted according to the physician s judgment to reach a target of 140/90 mm Hg. The use of all antihypertensive agents was permitted. Echocardiography was repeated after 1 year and after an average follow-up of 6.4 years (range: 3 to 11 years) in all of the patients with primary aldosteronism and in 108 of 274 patients with essential hypertension who were matched for age, gender, body mass index, and estimated duration of hypertension. Statistical Analysis This study had a statistical power of 95% to detect 20% differences between patients with primary aldosteronism and essential hypertension, with an -value of Variables are expressed as mean SD unless otherwise indicated. Continuous variables were compared by Student s t test. Variables with skewed distribution were analyzed after logarithmic transformation. Categorical variables were compared by the Pearson s 2 test. The relationships between different variables were examined by linear regression analysis, and the correlation was expressed by the correlation coefficient. Changes from the baseline of echocardiographic parameters were assessed by 2-way ANOVA. Multivariate discriminant analysis was performed to identify variables independently associated with changes in echocardiographic parameters after treatment. All of the tests for significance and resulting P values were 2 sided, with a level of significance of Results Adrenal adenoma was demonstrated in 29 (54%) of 54 patients with primary aldosteronism, whereas the remaining 25 (46%) had no evidence of adrenal masses. As shown in Table 1, patients with primary aldosteronism and essential hypertension had comparable heart rates, blood pressure levels, estimated durations of hypertension, plasma glucose, and plasma lipid profiles. As expected, patients with primary aldosteronism had significantly higher plasma aldosterone and lower plasma potassium and active renin levels than patients with essential hypertension. Baseline echocardiographic parameters are summarized in Table 2. The average LV internal dimensions and wall thickness had nonsignificant trends to higher values, and the LV mass and LVMI were significantly greater in patients with primary aldosteronism as compared with patients with essential hypertension. The left atrial diameter and the ratio of the posterior LV wall thickness to one half of the LV internal

3 Catena et al The Heart in Aldosteronism 913 Table 1. Baseline Characteristics of the Study Population Parameter Essential Hypertension (n 274) Primary Aldosteronism (n 54) P Clinical characteristics Age, y Female/male 82/192 16/ Body mass index, kg/m Heart rate, bpm Systolic blood pressure, mm Hg* Diastolic blood pressure, mm Hg* Estimated duration of hypertension, y Current smoking, (n) % 71 (26) 15 (28) Alcohol intake, g/d Laboratory variables Plasma glucose, mmol/l Total cholesterol, mmol/l HDL cholesterol, mmol/l Triglycerides, mmol/l Plasma sodium, mmol/l Plasma potassium, mmol/l Urinary sodium excretion, mmol/24 h Urinary potassium excretion, mmol/24 h Plasma aldosterone, pg/ml Plasma active renin, pg/ml Aldosterone:active renin ratio Values are mean SD unless otherwise indicated. P values are calculated by Student s t test. HDL indicates high-density lipoprotein. To convert to SI units, multiply active renin for 0.19 (ng ml 1 h 1 ) and aldosterone for 2.76 (pmol/l). *Blood pressure was measured after appropriate washout of antihypertensive drugs. Values are those that were measured before correction with oral supplementation. dimension were comparable in the 2 groups. The prevalence of LV hypertrophy and LV concentric geometry was, respectively, 33% and 26% in primary aldosteronism and 21% (P 0.05) and 24% (P 0.73) in essential hypertension, respectively. No significant differences of ejection fraction, endocardial FS, and midwall FS were observed between patients with primary aldosteronism and essential hypertension, indicating comparable systolic function. Both the ratio of E/A velocities and the deceleration time were significantly different in the 2 groups, indicating the presence of more severe diastolic dysfunction in primary aldosteronism. In primary aldosteronism, linear regression analysis showed that LVMI, but not the ratio of the posterior LV wall thickness to one half of the LV internal dimension, had a significant relationship with mean blood pressure measured both before (r 0.362; P 0.01) and after (r 0.319; P 0.05) drug washout, duration of hypertension (r 0.375; P 0.01), and plasma aldosterone concentrations (r 0.294; P 0.05); the ratio of E/A velocities was inversely related with duration of hypertension (r 0.391; P 0.01), LVMI (r 0.323; P 0.05), and plasma aldosterone (r 0.304; P 0.05) but not with blood pressure levels. In essential hypertension, LVMI had a statistically significant relationship with mean blood pressure (r 0.194; P 0.01), duration of hypertension (r 0.249; P 0.01), E/A ratio (r 0.233; P 0.01), and plasma aldosterone (r 0.134; P 0.05). No significant differences in echocardiographic parameters were observed between primary aldosteronism patients with or without computed tomography evidence of adrenal masses. Follow-Up Patients with primary aldosteronism were reassessed with echocardiography after treatment (adrenalectomy: n 24; spironolactone: n 30), at 1 year, and after an the average follow-up of 6.4 years. Antihypertensive medications used during the study are shown in Table 3. The frequency of the use of specific types of drugs was comparable in patients treated with adrenalectomy or spironolactone. Blood pressure declined significantly during the first year, with average values that, during the entire course of the study, were of 135/82 and 137/82 mm Hg in patients who were treated with adrenalectomy and spironolactone, respectively. Treatment was followed by normalization of blood pressure in 21 patients with primary aldosteronism (39%; adrenalectomy: n 10; spironolactone: n 11) and by significant improvement in the remaining 33 (61%; adrenalectomy: n 14; spironolactone: n 19; P 0.71). In the first year, plasma potassium increased significantly from baseline levels (from

4 914 Hypertension November 2007 Table 2. Baseline Echocardiographic Parameters of the Study Population Parameter Essential Hypertension (n 274) Primary Aldosteronism (n 54) P LVDd, mm LVDs, mm IVSd, mm PWd, mm RWTd LV mass, g LV mass/height 2.7, g/m Left atrium diameter, mm Ejection fraction, % Endocardial FS, % Endocardial FS, % of predicted value Midwall FS, % Midwall FS, % of predicted value E/A ratio E-deceleration time, ms Values are mean SD unless otherwise indicated. P values are calculated by Student s t test. LVDd indicates LV diastolic internal dimension; LVDs, left ventricular systolic internal dimension; IVSd, interventricular septum thickness; PWTd, posterior wall thickness; RWTd, relative wall thickness; LV mass/height 2.7, left ventricular mass indexed for height to the 2.7 power; mess, meridional end-systolic stress; cess, circumferential end-systolic stress; and E/A, early/late diastolic filling velocities to mmol/l; P 0.001) and remained stable thereafter. Markers of volume change, such as body weight (from to kg), packed cell volume (from 44 3 to44 3%), and serum albumin (from 41 2 to42 3 g/dl), did not change significantly during follow-up. Table 4 summarizes the echocardiographic measurements obtained at follow-up in patients with primary aldosteronism. During the initial 1-year period, average LV internal dimensions and wall thickness had a nonsignificant trend to decrease in all of the patients with primary aldosteronism. This trend was more evident in patients who were treated with Table 3. Antihypertensive Medications Used at Baseline and at End of Follow-Up Essential Hypertension (n 108) adrenalectomy as compared with patients treated with spironolactone and resulted in a decrease of the LV mass and LVMI that was significant only in the former group at this time point (Figure). Subsequent average changes in LV dimensions and wall thickness were greater in patients treated with spironolactone than in those who had adrenalectomy, with an overall change, from baseline to the end of follow-up, that tended to be greater, although nonsignificantly, in adrenalectomized patients. At the end of follow-up, the prevalence of LV hypertrophy and LV concentric geometry changed from 38% to 8% (P 0.05) and from 29% to 21% Primary Aldosteronism (n 54) End of Adrenalectomy Adrenalectomy End Spironolactone Spironolactone End Medication Baseline Study Baseline (n 24) of Study (n 24) Baseline (n 30) of Study (n 30) Diuretic, n (%) 49 (45) 60 (56) 13 (54) 3 (13) 16 (53) 3 (10) -Blocker, n (%) 46 (43) 55 (51) 13 (54) 3 (13) 14 (47) 5 (17) Calcium channel blocker, n (%) 51 (47) 67 (62) 13 (54) 6 (25) 15 (50) 7 (23) ACE inhibitor, n (%) 43 (40) 60 (56) 11 (46) 6 (25) 12 (40) 7 (23) Angiotensin receptor blocker, n (%) 13 (12) 22 (20) 4 (17) 2 (8) 5 (17) 4 (13) -Blocker, n (%) 3 (3) 4 (4) 5 (21) 0 5 (17) 0 Aldosterone antagonist, n (%) (100) Other antihypertensive agents, n (%) (8) 0 4 (13) 0 Drugs per patient * Total Use at the end of study was defined as receipt of the specific drug for 50% of follow-up visits. The average dose of spironolactone was 121 mg/d. Clinically relevant gynecomastia occurred in 4 of 21 male patients treated with this drug (19%) and responded well to reduction of dosage. ACE indicates angiotensin-converting enzyme. *Value is calculated without aldosterone antagonists.

5 Catena et al The Heart in Aldosteronism 915 Table 4. Echocardiographic Parameters of Patients With Primary Aldosteronism Who Were Treated With Adrenalectomy (n 24) or Spironolactone (n 30) at Baseline, After 1 Year, and at the End of Follow-Up Adrenalectomy Spironolactone Adrenalectomy End of Spironolactone End of Parameter Baseline at 1 Year Study P Baseline at 1 Year Study P LVDd, mm LVDs, mm IVSd, mm PWd, mm RWTd LV mass, g * * LV mass/height 2.7, g/m * * Left atrium diameter, mm Ejection fraction, % E/A ratio E-deceleration time, ms Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Plasma aldosterone, pg/ml Plasma active renin, pg/ml Values are mean SD unless otherwise indicated. P values are calculated by ANOVA. To convert to SI units, multiply active renin for 0.19 (ng ml 1 h 1 ) and aldosterone for 2.76 (pmol/l). *P 0.05 vs baseline. (P 0.44), respectively, in adrenalectomized patients, and from 30% to 7% (P 0.05) and from 23% to 20% (P 0.75), respectively, in patients treated with spironolactone. The E/A ratio and the deceleration time had nonsignificant trends to change after both adrenalectomy and spironolactone treatment, suggesting only partial recovery of the diastolic dysfunction after removal of the effects of excess aldosterone. The ratio of the posterior LV wall thickness to one half of the LV internal dimension and parameters of systolic function did not change significantly during the study. After 1 year, plasma renin levels increased significantly in both patients who were treated with adrenalectomy (from to Figure. Percentage changes of LVMI in the short- and long-term follow-up in patients with primary aldosteronism who were treated with adrenalectomy (n 24) or spironolactone (n 30). Short-term and long-term follow-up measurements were done after 1 year and after an average period of 6.4 years, respectively. *P 0.05 vs baseline; P 0.01 vs baseline pg/ml; P 0.01) and spironolactone (from to pg/ml; P 0.02); at the end of follow-up, renin levels were comparable in the 2 treatment groups ( and pg/ml, respectively; P 0.85). In both adrenalectomized and spironolactone-treated patients, the reduction of LVMI was directly correlated with changes in mean blood pressure (respectively: r 0.509, P 0.01 and r 0.427, P 0.05) and pretreatment plasma aldosterone concentrations (respectively: r 0.413, P 0.05 and r 0.391, P 0.05) but not with pretreatment plasma potassium and active renin. Multivariate analysis showed that changes in mean blood pressure (P 0.05) and pretreatment aldosterone levels (P 0.05) were both independent predictors of LVMI decrease after treatment, and their respective contributions were 47% and 24%. In 108 patients with essential hypertension, the average blood pressure during follow-up was 137/ 81 mm Hg, and the decrease in LVMI ( 11.8%) was significantly smaller than in patients with primary aldosteronism ( 17.4%; P 0.05), whereas the frequency of reversal of LV hypertrophy (essential hypertension: from 22% to 8%; primary aldosteronism: from 33% to 7%) did not differ significantly between the groups (P 0.19). Discussion Increased LV mass and impaired LV diastolic filling have been reported in patients with primary aldosteronism and might predispose these patients to cardiac complications. Our study has examined the long-term echocardiographic evolution in a large cohort of patients with primary aldosteronism after treatment. Results demonstrate that adrenalectomy and spironolactone are both effective in decreasing the LV mass, although this effect occurs earlier after surgical treatment. In

6 916 Hypertension November 2007 both treatment groups, the LV diastolic filling pattern had only mild and nonsignificant improvement. Pretreatment plasma aldosterone concentrations predict LVMI decrease during follow-up, independent of treatment-related blood pressure changes. A growing body of evidence links aldosterone to development and/or progression of cardiovascular disease, seemingly separate from its effects on blood pressure. In fact, animal and human studies support the contention that cardiac damage in aldosteronism is not just the result of a pressure-volume overload but might involve additional endocrine and paracrine mechanisms. 2,3 Many cross-sectional echocardiographic evaluations have reported an excess increase of LV mass in patients with primary aldosteronism as compared with other types of hypertensive disease, 8 15 although this finding has not been confirmed in other studies Disparity of the findings could be ascribed to the limited sample size of some studies and differences in the severity and duration of hypertension in selected patients and respective control subjects. The present study has been conducted in a large cohort of patients with primary aldosteronism who were diagnosed using standardized procedures that were homogeneously applied by the same physicians. 21 This practice, together with the collection of data in a single database, should have limited any possible selection bias. Moreover, patients with primary aldosteronism have been compared with patients with essential hypertension who were appropriately matched for age, sex, severity, and estimated duration of hypertension and who had comparable cardiovascular risk profiles. Our results confirm the presence of greater LV mass and more prevalent LV hypertrophy in patients with primary aldosteronism that is associated with evidence of an abnormal pattern of LV diastolic filling, such as that reported in previous studies, 10,11 but not with changes of LV geometry and systolic function. Measurement of increased LV mass in patients with primary aldosteronism might reflect the increased circulating volume resulting from the renal effects of the hormone. However, we have observed greater differences in wall thickness than ventricular volumes between patients with primary aldosteronism and essential hypertension at baseline and greater changes in wall thickness than ventricular volumes after both surgical and medical treatment of primary aldosteronism. This would suggest that the contribution of volume factors is not predominant over other factors and that cardiac changes, in this condition, could not simply be explained by the salt- and water-retaining effects of aldosterone. The cardiac hemodynamic overload is not the only determinant of LV hypertrophy, and various hormones can play specific roles in different subsets of hypertension. The renin-angiotensin-aldosterone system is an important contributor to the pathogenesis of LV hypertrophy, 37 and primary aldosteronism permits evaluation of the cardiac effects of elevated aldosterone independent from those of angiotensin. LV hypertrophy is an important independent predictor of major cardiovascular events 38 in hypertension, and increased LV mass in patients with primary aldosteronism might be associated with worse cardiovascular outcome in comparison with other hypertensive groups. Relevant to this point, a recent retrospective study of a large cohort of patients with adrenal adenoma or idiopathic aldosteronism has reported an excess rate of cardiovascular complications and LV hypertrophy in comparison with properly matched patients with essential hypertension. 39 Cross-sectional evidence of associations between cardiac phenotypes and possible causative factors is of limited value, and findings should be confirmed in longitudinal evaluations. The few echocardiographic observations of cardiac changes after treatment of aldosteronism are confined to short-term follow-up studies, mostly after removal of an adrenal adenoma. 9,10,18 The present study is the first to provide data of a long-term echocardiographic follow-up in a substantial cohort of patients with primary aldosteronism after either surgical or medical treatment. Our 11-year study demonstrates that patients treated with either adrenalectomy or spironolactone have significant decrease of LVMI, a response that occurs within the first year only after surgical treatment. In both treatment groups, baseline LVMI was directly correlated with plasma aldosterone concentration, and this concentration was an independent predictor of changes of LVMI after treatment. Data demonstrate that the decrease of LVMI is only partially explained by blood pressure changes, suggesting a role of aldosterone that is independent from the hemodynamic overload. This possibility would also be supported by the observation that, in patients with essential hypertension, the decrease of LVMI that occurred during follow-up in the presence of very similar blood pressure values was significantly smaller than in patients with primary aldosteronism. Mineralocorticoid receptors have been demonstrated in human cardiomyocytes, 40 and their activation might play a role in myocardial hypertrophy and cardiac remodeling 41 in patients with primary aldosteronism via mechanisms that include modulation of ionic movements 42 and accelerated fibrosis. 43 The latter mechanism might, in turn, result from interactions of aldosterone with angiotensin, endothelin, and bradykinin; activation of inflammatory cells; and stimulation of fibroblast proliferation and collagen synthesis (reviewed in References 41 and 43). Interruption of these receptormediated mechanisms might explain why, in the long term, treatment of primary aldosteronism with aldosterone receptor antagonists has comparable effects to the removal of an aldosterone-secreting adenoma in reducing LV mass, although this response occurs later than after the removal of excess circulating aldosterone by adrenalectomy. From a pathophysiological point of view, persistent hyperaldosteronemia with possible involvement of nongenomic effects of aldosterone 2,3 might hypothetically explain why regression of LV hypertrophy requires a longer time to occur in patients treated with spironolactone than in those treated with surgery. Consistent with our findings, favorable effects of mineralocorticoid antagonists on reduction of LV mass have been reported in patients with essential hypertension and LV hypertrophy. 44 In these patients, effects of aldosterone antagonists resulted to be additive with those of angiotensinconverting enzyme inhibitors and, therefore, independent from the renin-angiotensin axis. In the present study, no patient in the essential hypertension group was treated with spironolactone.

7 Catena et al The Heart in Aldosteronism 917 Some limitations of our study need to be highlighted. First, given that we performed selective adrenal vein sampling in only 14 of our patients and, instead, mainly relied on computed tomography and adrenal scintigraphy for subtype differentiation, it is possible that we have misclassified some patients with aldosterone-producing adenoma as idiopathic hyperplasia or vice versa. More accurate detection of truly unilateral forms of primary aldosteronism may have resulted in better blood pressure and echocardiographic responses to adrenalectomy than were seen in this study. Second, the majority of patients were on treatment at the time of study, and the use of certain antihypertensive medications during follow-up might have influenced the echocardiographic evolution. For instance, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers could be more effective than other agents in reducing the LV mass, 45 but frequency of the use of these drugs was comparable in patients treated with adrenalectomy or spironolactone. Nonetheless, differences in the pretreatment status and in drugs used at baseline and during follow-up might have had significant impact on the cardiac outcome of the study patients. Third, the doses of spironolactone that have been used in this study are higher than those that are currently recommended for medical treatment of primary aldosteronism, and, therefore, extrapolation of the results to a more general context should be done with caution. With regard to this issue, further investigation of the cardiac effects of the newer aldosterone-receptor antagonists, such as eplerenone, which offer the opportunity to use relatively higher doses without antiandrogenic effects, is warranted. Last, our study might have underestimated the impact of blood pressure on cardiac structure, because we did not include measurements of the 24-hour blood pressure profile, which is superior to clinic blood pressure for the prediction of LV mass. 46 Results of previous studies with ambulatory blood pressure monitoring in primary aldosteronism are controversial, with some studies reporting significant differences with essential hypertension 47,48 and others not supporting this contention. 11,15 In our hands, comparison of ambulatory blood pressure profiles in subsets of the primary aldosteronism (n 32) and essential hypertension (n 153) group did not show significant differences. Perspectives Recovery of cardiac anatomic and/or functional abnormalities and prevention of cardiovascular events are primary goals of treatment in hypertensive patients. Primary aldosteronism was once considered to account for 1% of all forms of hypertension, but recent work suggests that it might be the most common curable cause, worth screening for in patients with high blood pressure and an index of suspicion, including those with hypokalemia and/or resistance to treatment. This study presents evidence that primary aldosteronism is associated with LV hypertrophy out of proportion to blood pressure levels that benefits substantially from treatment in the long term. In this view, adrenalectomy and mineralocorticoid receptor blockade appear to be of considerable therapeutic value inasmuch as they significantly reduce LV mass, whereas their beneficial effect on the LV diastolic filling pattern is only partial. These findings underscore the importance of a timely identification of this endocrine disorder to obtain regression of cardiac abnormalities. Future studies will have to address the potential benefits of the newest mineralocorticoid receptor antagonists on cardiac structural and functional abnormalities of primary aldosteronism and to clarify whether these therapeutic interventions can effectively prevent late cardiovascular complications. Sources of Funding This work was supported by research grants from the Italian Ministry of the University and Scientific and Technologic Research (to L.A.S. and C.C.) and by research grants from the Italian Society of Hypertension (to G.L.C. and E.N.). None. Disclosures References 1. Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone. J Am Soc Nephrol. 2004;15: Rossi GP, Boscaro M, Ronconi V, Funder JW. Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab. 2005;16: Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann N Y Acad Sci. 2002;970: Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341: 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: (Correction. 2003;348: 2271). 6. Plouin PF, Amar L, Chatellier G; for the COMETE-Conn Study Group. Trends in the prevalence of primary aldosteronism, aldosteroneproducing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant. 2004;19: Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89: Janota T, Hradec J, Kral J. Heart in adrenal disease. Cor Vasa. 1992;34: Denolle T, Chatellier G, Julien J, Battaglia C, Luo P, Plouin PF. Left ventricular mass and geometry before and after etiologic treatment in renovascular hypertension, aldosterone-producing adenoma, and pheochromocytoma. Am J Hypertens. 1993;6: Rossi GP, Sacchetto A, Visentin P, Canali C, Graniero GR, Palatini P, Pessina AC. Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension. 1996;27: Rossi GP, Sacchetto A, Pavan E, Palatini P, Graniero GR, Canali C, Pessina AC. Remodeling of the left ventricle in primary aldosteronism due to Conn s adenoma. Circulation. 1997;95: Shigematsu Y, Mareomi H, Hideki O, Hara Y, Hayashi Y, Kodama K, Katsuhiko K, Hiwada K. Left ventricular hypertrophy precedes other target-organ damage in primary aldosteronism. Hypertension. 1997;29: Tanabe A, Naruse M, Naruse K, Hase M, Yoshimoto T, Tanaka M, Seki T, Demura R, Demura H. Left ventricular hypertrophy is more prominent in patients with primary aldosteronism than in patients with other types of secondary hypertension. Hypertens Res. 1997;20: Rossi GP, Di Bello V, Ganzaroli C, Sacchetto A, Cesari M, Bestini A, Giorni D, Scognamiglio R, Mariani M, Pessina AC. Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension. 2002;40: Matsumura K, Fujii K, Oniki H, Oka M, Iida M. Role of aldosterone in left ventricular hypertrophy in hypertension. Am J Hypertens. 2006;19: Suzuki T, Abe H, Nagata S, Saitoh F, Iwata S, Ashizawa A, Kuramochi M, Omae T. Left ventricular structural characteristics in unilateral reno-

8 918 Hypertension November 2007 vascular hypertension and primary aldosteronism. Am J Cardiol. 1988; 62: Yoshihara F, Nishikimi T, Yoshitomi Y, Nakasone I, Abe H, Matsuoka H, Omae T. Left ventricular structural and functional characteristics in patients with renovascular hypertension, primary aldosteronism and essential hypertension. Am J Hypertens. 1996;9: Yoshitomi Y, Nishikimi T, Abe H, Yoshimar F, Suzuki T, Ashizawa A, Nagata S, Kuramochi M, Matsuoka H, Omae T. Comparison of changes in cardiac structure after treatment in secondary hypertension. Hypertension. 1996;27: Rizzoni D, Muiesan ML, Porteri E, Salvetti M, Castellano M, Bettoni G, Tiberio G, Giulini SM, Monteduro C, Garavelli G, Agabiti-Rosei E. Relations between cardiac and vascular structure in patients with primary and secondary hypertension. J Am Coll Cardiol. 1998;32: Goldkorn R, Yurenev A, Blumenfeld J, Fishman D, Devereux RB. Echocardiographic comparison of left ventricular structure and function in hypertensive patients with primary aldosteronism and essential hypertension. Am J Hypertens. 2002;15: 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: Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Novello M, Favret G, Melis A, Cavarape A, Sechi LA. Insulin sensitivity in patients with primary aldosteronism: a follow-up study. J Clin Endocrinol Metab. 2006;91: The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993;153: Ferrari P, Shaw SG, Nicod J, Saner E, Nussberger J. Active renin versus plasma renin activity to define aldosterone-to-renin ratio for primary aldosteronism. J Hypertens. 2004;22: Kem DC, Weinberger MH, Mayes DM, Nugent CA. Saline suppression of plasma aldosterone in hypertension. Arch Intern Med. 1971;128: Grim CE, Weinberger MH, Higgins JT, Kramer NJ. Diagnosis of secondary forms of hypertension. A comprehensive protocol. JAMA. 1977; 237: Sahn DJ, DeMaria A, Kisslo J, Weyman A. The committee on M-mode standardization of the American Society of Echocardiography: recommendations regarding quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements. Circulation. 1978;58: Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I, Laragh JH. Patterns of left ventricular hypertrophy and geometric remodeling in arterial hypertension. J Am Coll Cardiol. 1992;19: Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57: de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and of the impact of overweight. J Am Coll Cardiol. 1992;20: Devereux RB, Roman MJ. Evaluation of cardiac and vascular structure by echocardiography and other noninvasive techniques. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, Treatment. 2nd ed. New York, NY: Raven Press; 1995: Reichek N, Wilson J, St John Sutton M, Piappert PA, Goidberg S, Hirshfeld JW. Noninvasive determination of left ventricular end-systolic stress: validation of the method and initial application. Circulation. 1982; 65: Gaasch WH, Zile MR, Hosino PK, Apstein CS, Blaustein AS. Stressshortening relations and myocardial blood flow in compensated and failing canine hearts with pressure-overload hypertrophy. Circulation. 1989;79: de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH, Laragh JH. Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol. 1994;23: Devereux RB, de Simone G, Pickering TG, Schwartz JE, Roman MJ. Relation of left ventricular midwall function to cardiovascular risk factors and arterial structure and function. Hypertension. 1998;31: Quinones MA, Otto C, Stoddard M, Waggoner A, Zoghbi W. Recommendations for quantifications of Doppler echocardiography: a report from the Doppler quantification Task Force for the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr. 2002;15: Morgan HE, Baker KM. Cardiac hypertrophy: mechanical, neural, and endocrine dependence. Circulation. 1991;83: Casale PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH. Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med. 1986;105: Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45: Lombes M, Alfaidy N, Eugene E, Lessana A, Farman N, Bonvalet JP. Prerequisite for cardiac aldosterone action: mineralocorticoid receptor and 11- -hydroxysteroid dehydrogenase in the human heart. Circulation. 1995;92: Schmidt BMW, Schmieder RE. Aldosterone-induced cardiac damage: focus on blood pressure independent effects. Am J Hypertens. 2003;16: Kometiani P, Gnudi L, Kahn BB, Askari A, Xie Z. Multiple signal transduction pathways link Na/K-ATPase to growth-related genes in cardiac myocytes. The role of Ras and mitogen-activated protein kinases. J Biol Chem. 1998;273: Funder J. Mineralocorticoids and cardiac fibrosis: the decade in review. Clin Exp Pharmacol Physiol. 2001;28: 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: Devereux RB. Therapeutic options in minimizing left ventricular hypertrophy. Am Heart J. 2000;139:S9 S Mancia G, Zanchetti A, Agabiti-Rosei E, Benemio G, De Cesaris R, Fogari R, Pessina A, Porcellati C, Rappelli A, Salvetti A, Trimarco B. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation. 1997;95: Ceruti M, Petramala L, Cotesta D, Cerci S, Serra V, Caliumi C, Iorio M, De Toma G, Ciardi A, Vitolo D, Letizia C. Ambulatory blood pressure monitoring in secondary arterial hypertension due to adrenal diseases. J Clin Hypertens. 2006;8: El-Gharbawy AH, Nadig VS, Kotchen JM, Grim CE, Sagar KB, Kaldunski M, Hamet P, Pausova Z, Gaudet D, Gossard F, Kotchen TA. Arterial pressure, left ventricular mass, and aldosterone in essential hypertension. Hypertension. 2001;37: