Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy

AJH

2003; 16:781–788

Review

Aldosterone Breakthrough During AngiotensinConverting Enzyme Inhibitor Therapy Atsuhisa Sato and Takao Saruta The effectiveness of angiotensin-converting enzyme (ACE) inhibitors in the treatment of cardiac diseases after infarction and heart failure, and of renal disease such as diabetic nephropathy, has been reported from recent largescale clinical trials on ACE inhibitors. However, effects of ACE inhibitors during long-term therapy have not always been optimal. In recent years, aldosterone breakthrough has been suggested as a factor potentially involved, in that aldosterone levels may not remain suppressed when an ACE inhibitor is given for a relatively long time, with circulating aldosterone concentrations perhaps increasing above pretreatment levels. To improve our understanding of aldosterone-induced organ damage, which has attracted much attention in recent years, we summarize the data on

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aldosterone breakthrough during ACE inhibitor treatment in various diseases, and then we consider the mechanism and clinical significance of aldosterone breakthrough. Given the wide range of indications for ACE inhibitors, further studies should be designed to examine in which diseases and for which types of patients aldosterone blockade will be indicated. At present, the mechanisms of aldosterone breakthrough remain obscure, requiring further studies, including those on regional nonepithelial effects of aldosterone. Am J Hypertens 2003;16:781–788 © 2003 American Journal of Hypertension, Ltd. Key Words: Aldosterone breakthrough, angiotensinconverting enzyme inhibitors, aldosterone blockade.

rom the standpoint of organ protection, the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in the treatment of cardiac diseases after infarction and heart failure, and of renal disease such as diabetic nephropathy, has been reported from recent largescale clinical trials on ACE inhibitors.1–5 However, effects of ACE inhibitors during long-term therapy have not always been optimal.6 In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial, 36% of the patients died within 1 year, and the overall survival time during the 10-year follow-up was only 260 days.7 Moreover, it was noted that the effect of ACE inhibitor on reducing urinary protein excretion in nephropathy was not as marked as expected.8 In recent years, aldosterone breakthrough has been suggested as a factor potentially involved, in that aldosterone levels may not remain suppressed when an ACE inhibitor is given for a relatively long time, with circulating aldosterone concentrations perhaps increasing above pretreatment levels. The Randomized Aldactone Evaluation Study (RALES), a recently published large-scale clinical trial in heart failure patients, showed the clinical usefulness of

mineralocorticoid receptor (MR) blockade,9 and clearly aldosterone breakthrough is not limited to patients with heart failure. To improve our understanding of aldosterone-induced organ damage, which has attracted much attention in recent years, we summarize the data on aldosterone breakthrough during ACE inhibitor treatment in various diseases, and then we review the mechanism and clinical significance of aldosterone breakthrough. In addition, aldosterone breakthrough is clearly different from the state of maintaining a high aldosterone concentration. In fact, plasma aldosterone concentrations remain commonly within the so-called normal range. Therefore, it is the occurrence of aldosterone breakthrough itself that is problematic, rather than the absolute plasma aldosterone concentration. Furthermore, it is also important to consider the expected effects of concomitant treatment with diuretics on aldosterone breakthrough because homeostatic mechanisms are activated as heart failure or hypertension treated by diuretics with reduced plasma volume, blood pressure (BP), and activation of the sympathetic nervous system.

Received February 5, 2003. First decision March 12, 2003. Accepted April 1, 2003.

versity, Tokyo, Japan. Address correspondence and reprint requests to Dr. Atsuhisa Sato, Department of Internal Medicine, Mito Red Cross Hospital, 3-12-48 San-nomaru, Mito city, Ibaraki, 310-0011, Japan; e-mail: atsu-sa@ pb3.so-net.ne.jp

From the Department of Internal Medicine (AS), Mito Red Cross Hospital, Ibaraki, and Department of Internal Medicine (TS), Keio Uni© 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.

0895-7061/03/$30.00 doi:10.1016/S0895-7061(03)00913-0

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FIG. 1. Changes in the plasma aldosterone concentration (PAC) and the plasma angiotensin II concentration (PA II), as compared with their corresponding control (placebo) levels, at various intervals during chronic treatment with the angiotensin-converting enzyme inhibitor captopril. The number of patients (n) is indicated for each treatment period. *P ⬍ .05 v the corresponding control level during the placebo period.15 (Reprinted with permission from Staessen J: Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 1981;91:457– 465.)

Definition The definition of aldosterone breakthrough is of critical importance; to date its definition has differed from study to study. Aldosterone breakthrough is generally considered as an elevation of plasma aldosterone concentration after treatment, compared with the pretreatment value.10,11 Some investigators, however, define aldosterone breakthrough as an aldosterone concentration exceeding the normal range established by their institution. Therefore, plasma aldosterone concentrations considered as aldosterone breakthrough differ greatly between studies. Aldosterone concentrations in circulating blood in patients with aldosterone breakthrough are generally thought to be derived from adrenal secretion. Recently, however, the potential of local synthesis of aldosterone, particularly in the heart and blood vessels, has been reported,12,13 and thus it is possible that local aldosterone production is involved in aldosterone breakthrough. In contrast, some researchers argue against a paracrine/endocrine role for locally produced aldosterone, in that the pathophysiologic effects of aldosterone in experimental models, which are largely blocked by the MR antagonist, are completely abolished by adrenalectomy.14 If the latter is the case, it is clearly important to clarify how regulation of aldosterone synthesis in the adrenal gland is involved as a causative mechanism in aldosterone breakthrough. Aldosterone breakthrough can be thought of as a state of sustained aldosterone synthesis in the adrenal glands during relative long-term ACE inhibitor therapy compared with pretreatment levels.

Aldosterone Breakthrough in Various Diseases Hypertension At the present time, the aldosterone breakthrough in patients with chronic heart failure during treatment with an ACE inhibitor has attracted clinical attention, and the RALES trial has revealed the importance of this phenomenon in the presence of heart failure.9 Such a breakthrough, however, was first reported in hypertensive patients. Soon after the introduction of captopril to clinical practice, it was shown that blood aldosterone was no longer suppressed when the ACE inhibitor was administered for a relatively long time.15,16 Staessen et al15 administered captopril to 7 patients with essential hypertension, and measured plasma angiotensin II (Ang II) concentrations over time. They noted that the plasma aldosterone concentration significantly decreased after 1 month compared with the pretreatment level, but returned to almost the same level as the pretreatment level at 6 months, and further increased thereafter, whereas the Ang II concentration was continuously suppressed until 12 months after the start of treatment (Fig. 1). During this time, BP was generally satisfactorily controlled, and urinary sodium/potassium excretions remained unchanged. Lijnen et al16 reported similar results after 1 year of treatment, also with captopril. We also observed aldosterone breakthrough in 38 of 75 patients with untreated essential hypertension (51%) after 40 weeks of ACE inhibitor therapy.17 In this study, we used three ACE inhibitors (enalapril, imidapril, trandolapril) but observed no significant difference in the incidence

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of breakthrough among these three drugs. Even when we used a clinically allowable maximum dose, aldosterone breakthrough occurred. Chronic (Congestive) Heart Failure The importance of aldosterone breakthrough in patients with chronic heart failure during ACE inhibitor therapy was first recognized in the RALES trial.9 When MacFadyen et al18 treated 91 patients with heart failure using five different ACE inhibitors, they found a reactivation of Ang II in 15% of patients, and aldosterone breakthrough in 38%, but no correlation between plasma aldosterone concentrations and serum ACE activity or plasma Ang II concentrations. Roig et al19 reported that treatment with ACE inhibitor for 6 months increased plasma Ang II concentrations in 50% of patients. When Tang et al20 administered enalapril to patients with heart failure at either a high (40 mg/day) or low dose (5 mg/day) for 34 weeks, they noted aldosterone breakthrough in 39% of the low dose group and 30% of the high dose group, with no intergroup differences, whereas the serum ACE activity remained suppressed. In patients with severely impaired cardiac function, aldosterone metabolic clearance decreased, indicating a probable mechanism for further increases in plasma aldosterone concentration. Acute Myocardial Infarction Borhgi et al21 reported that plasma aldosterone concentrations were suppressed during the first 3 months of ACE inhibitor therapy, but returned to baseline levels thereafter in 10 patients with acute myocardial infarction (AMI), although their serum ACE activity remained suppressed at 6 months after the start of ACE inhibition and canvassed the possible involvement of aldosterone breakthrough in BP control in such patients. Although there have been relatively few long-term studies on aldosterone breakthrough in patients with AMI, recently the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial has been closed. This is a large-scale clinical trial on a new aldosterone blocker (eplerenone) in patients with AMI and heart failure due to left ventricular (LV) systolic dysfunction. More than 6000 patients have been enrolled to determine whether aldosterone blockade improves survival rate.22 Although it has been reported that aldosterone synthesis in rats may decrease in the adrenal glands after AMI but increase in the heart,23 it is unclear whether this is also true for humans, requiring further studies to clarify the presence or absence of local aldosterone synthesis in the heart. Diabetic Nephropathy Administration of an ACE inhibitor is recommended for the treatment of hypertension occurring with diabetes, particularly for patients developing nephropathy. However, Shiigai and Shichiri8 recently showed that such a renoprotective effect was transient in many patients when

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urinary protein excretion was used as an indicator, with urinary protein excretion beginning to increase again during a relatively long period of ACE inhibitor therapy. When we administered trandolapril for 40 weeks to 45 patients with early diabetic nephropathy, aldosterone breakthrough was observed in 18 (40%).24 This is evidence for the appearance of this phenomenon even in patients with diabetic nephropathy.

Clinical Meaning Experimental studies have shown that target organ damage in the cardiovascular system can be independent of BP, in rats given aldosterone on a high salt diet.25 Moreover, aldosterone-induced vasculitis may underlie progressive cardiac and renal diseases.26 Clinical studies in patients with chronic heart failure show that the higher the plasma aldosterone concentration, the higher the mortality,27 with particularly high plasma aldosterone concentrations seen in “cardiac cachexia.” Plasma aldosterone levels, however, increase in human heart failure only after diuretics are introduced. The more severe heart failure brings about the more vigorous diuretics used, which results in the lower BP, the greater the sympathetic stimulation, higher plasma Ang II and aldosterone, and poorer prognosis. Therefore, the role of diuretics in such poor prognosis in relation with higher plasma aldosterone levels must be considered. The failure of ACE inhibitors to suppress aldosterone production during a long period often results in no blockade of the cardiovascular effect of aldosterone, therefore aldosterone breakthrough may become extremely significant from the standpoint of organ protection. The RALES trial clearly confirmed the usefulness of blockade against the effect of breakthrough of aldosterone in at least 30% of patients with chronic heart failure.9 This, however, reflects overall results, and in some clinical cases ACE inhibitor can continuously suppress plasma aldosterone concentration. Although comparison between groups of patients with and without aldosterone breakthrough is required to clarify the clinical significance of breakthrough in individual cases, such comparison has been rarely performed. It has been reported that there are no significant differences in general laboratory test results, clinical findings, or ACE inhibitor doses between patients with and without aldosterone breakthrough.15–17 Even in the presence of aldosterone breakthrough, BP may be satisfactorily controlled,15–17,24,28 which may be one of the reasons why the phenomenon has not attracted more attention until the present time. Borghi et al21 suggested the possible involvement of aldosterone breakthrough in BP control in AMI patients. Cicoira et al29 observed aldosterone breakthrough in about 10% of the patients examined, and noted a correlation with functional status, in terms of a decrease in exercise capacity in such patients. We17 reported no improvement of LV hypertrophy in patients with essential hypertension and aldosterone breakthrough, although their BP was satisfactorily con-

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FIG. 2. Changes in PAC and left ventricular mass index (LVMI) before and after antihypertensive treatment with an angiotensin-converting enzyme inhibitor in patients with essential hypertension with left ventricular hypertrophy, in the group without aldosterone breakthrough (A) and in the group with aldosterone breakthrough (B). Values are mean ⫾ SD. *P ⬍ .05 v baseline value.17 Other abbreviations as in Fig. 1. (Reprinted with permission from Sato A: Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001;29:13–21.)

trolled (Fig. 2). Moreover, no improvement in urinary protein excretion was seen in diabetic nephropathy in patients on an ACE inhibitor and with aldosterone breakthrough (Table 1).24 These findings underscore the clinical importance of the effects of breakthrough aldosterone on both the heart and the kidneys. Our studies also suggest the possibility that attenuation of the aldosterone effects may become a new goal for the patients with essential hypertension with LV hypertrophy or early diabetic nephropathy who show aldosterone breakthrough during ACE inhibitor treatment and have escaped the organ protective effects of ACE inhibitors.

Mechanisms The mechanisms of aldosterone breakthrough during ACE inhibitor therapy are briefly discussed by dividing them into 1) insufficient inhibition on ACE activity, 2) an effect of Ang II independent of ACE activity, and 3) other mechanisms. Insufficient Inhibition of ACE Activity Inhibition on ACE activity is clearly insufficient when an ACE inhibitor is used at a clinically insufficient dose, resulting in no inhibition of either Ang II or aldosterone.20 When Farquharson and Struthers30 administered lisinopril to patients with heart failure for 18 months, and examined the conversion of Ang I to Ang II in the vascular wall as an indicator of ACE inhibition, they observed decreased ACE inhibition over time, whereas the heart failure status remained stable. In another study31, the ACE activity in

the ventricles remained unchanged, even after long-term ACE inhibitor therapy, compared with pretreatment levels. In contrast, Jorde et al32 reported that the ACE activity was completely inhibited in 23 of 34 patients examined, Table 1. Clinical data of patients with type 2 diabetes and early nephropathy treated with an angiotensin-converting enzyme inhibitor for 40 weeks: with or without aldosterone breakthrough24 Characteristic Number (men/women) Age (yr) Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min) Na (mEq/L) K (mEq/L) BUN (mg/dL) Cr (mg/dL) UAE (mg/g Cr) PRA (ng/mL/h) PAC (pg/mL) HbA1c (%)

Breakthrough (ⴚ)

Breakthrough (ⴙ)

27 (15/2) 64 ⫾ 12

18 (10/8) 61 ⫾ 10

136 ⫾ 13

135 ⫾ 12

84 ⫾ 11

83 ⫾ 10

73 142.5 4.1 13.5 0.88 119 3.98 53.2 7.2

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

3 1.8 0.3 1.8 0.25 95 1.66 15.1 0.4

72 142.3 4.3 12.8 0.90 368 3.15 112.0 7.1

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

3 1.6 0.2 1.3 0.20 142* 1.58 18.7* 0.3

BP ⫽ blood pressure; BUN ⫽ blood urea nitrogen; Cr ⫽ creatinine; UAE ⫽ urinary albumin excretion; PRA ⫽ plasma renin activity; PAC ⫽ plasma aldosterone concentration. All values are mean ⫾ SD. * P ⬍ .05 v the value in the group without aldosterone breakthrough.

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with the degree of ACE inhibition during therapy determined from the ratio of the pressor response to Ang I and Ang II as an indicator, and showing no correlation with plasma aldosterone concentrations. They also reported that the ACE activity was completely inhibited in 64% of patients with increased plasma aldosterone concentrations, and that the degree of ACE inhibition was not correlated with plasma aldosterone. We also reported similar results in patients with essential hypertension. Plasma aldosterone concentrations are eventually independent of ACE activity in patients with essential hypertension, and plasma aldosterone concentrations tend to increase with the duration of ACE inhibitor treatment, although this increase does not reflect a reduced inhibition of ACE activity.33 Therefore, insufficient inhibition of ACE activity cannot explain the entire mechanism of aldosterone breakthrough. Although it has been reported that ACE activity increases in the heart in heart failure,34 the amount of ACE inhibitor required to completely inhibit such ACE activity has not been clearly demonstrated. From the results of the Assessment of Treatment with Lisinopril and Survival (ATLAS) study,35 it has been inferred that aldosterone may be inhibited by increasing the dose of ACE inhibitor. In contrast, however, plasma aldosterone concentrations cannot be suppressed by ACE inhibitors at the doses currently used in clinical practice. Effect of Ang II Independent of ACE Activity Arguments about the ACE activity-independent effect of Ang II can be divided as follows: 1) ACE inhibitors cannot inhibit aldosterone production because they cannot block Ang II synthesis through non-ACE pathways; therefore, angiotensin type 1 (AT1) receptor blockers (ARB), which block the effect of Ang II at the receptor level, are to be preferable; and 2) aldosterone production cannot be inhibited even by an ARB, indicating the importance of regulations other than Ang II. It has been reported that the vascular response to Ang I can be blocked in patients with coronary heart disease or chronic heart failure when an ACE inhibitor is combined with a chymase inhibitor,36 and in the human heart, Ang II synthesis is almost completely achieved with chymase.37,38 Studies in patients with hypertension (including those with renovascular or renal hypertension), or in heart failure, have shown that plasma aldosterone concentrations can be reduced by an ACE inhibitor for a short time (3 to 10 days),39 – 43 and that such reduction is strongly related to the suppression of plasma Ang II.44 During such therapeutic course, aldosterone is suppressed even if the serum potassium concentration increases, indicating that the effect on Ang II clearly has a major role in aldosterone suppression.40,41,43 In the CONSENSUS trial, plasma Ang II concentrations were significantly suppressed at week 6,

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and plasma aldosterone concentrations measured simultaneously were also suppressed.27 It has been reported that when an ACE inhibitor is administered for a relatively long time, plasma Ang II concentrations may increase, reaching levels higher than pretreatment.45,46 At 6 months of enalapril treatment, Ang II concentrations returned to pretreatment levels, as did plasma aldosterone concentrations in parallel with the increase in Ang II.28,47 From these studies, Ang II generally appear to be blocked by ACE inhibitors for a short time after initiation of therapy, with aldosterone production simultaneously inhibited. However, suppression of Ang II by ACE inhibitors is overcome when therapy is relatively prolonged, and aldosterone breakthrough correspondingly may appear. It is unclear the extent to which ACE or chymase are involved in Ang II synthesis during the course of these events. However, the results of a number of studies suggest the presence of mechanisms that cannot be explained by the effect of Ang II through the AT1 receptor alone. When Roig et al19 administered an ACE inhibitor to patients with chronic heart failure for 6 months, they observed restoration of blood Ang II concentrations in 50% of the patients examined, but not any significant difference in plasma aldosterone concentrations between patients with and without Ang II inhibition. Grossman et al48 saw aldosterone breakthrough in patients with essential hypertension, even when treated with the ARB losartan. Furthermore, aldosterone breakthrough was also observed in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial in patients with congestive heart failure treated with the ARB candesartan.49 Naruse et al50 carried out a fundamental study on rats, and observed aldosterone breakthrough with candesartan with at three times the sufficient antihypertensive dose. Therefore, it is difficult to explain the aldosterone breakthrough during ACE inhibitor therapy uniquely by the effects of Ang II through AT1 receptors at the present time. However, a possible role for Ang II action by AT2 receptors is worthy of consideration to explain why ARB may not work to lower plasma aldosterone concentrations. Naruse et al50 reported that aldosterone breakthrough occurred during long-term ARB candesartan therapy in stroke-prone spontaneously hypertensive rats, and when they administered an AT2 receptor antagonist concomitantly with candesartan, plasma aldosterone concentrations were significantly decreased. Whether aldosterone breakthrough occurs through AT2 receptors in humans, however, awaits further investigation. Renin secretion is under negative feedback regulation by the AT1 receptors on juxtaglomerular cells.51 Therefore, it is expected that plasma renin would be increased during long-term administration of ACE inhibitors, resulting in an increased generation of Ang II. Even if so, how increased Ang II regulates aldosterone production remains uncertain.

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Other Mechanisms Adrenocorticotropic Hormone There are rare reports on changes in plasma (adrenocorticotropic hormone [ACTH]) concentrations during ACE inhibitor therapy, which show no significant changes in plasma cortisol concentrations during ACE inhibition,39,42 and thus little possibility of involvement of ACTH in aldosterone breakthrough. Even if the plasma ACTH concentrations were increased, stimulation of aldosterone secretion by ACTH is transient, with repeated or chronic administration of ACTH reported to suppress aldosterone secretion.52,53 There is no evidence that physiologic levels of ACTH suppress aldosterone. The corticotropin-releasing hormone (CRH) administration or stresses that cause ACTH secretion increase circulating aldosterone levels,54 an effect that is blocked by hypophysectomy. However, the role of ACTH in aldosterone secretion is minor. Aldosterone secretion usually remains normal after hypophysectomy, because the reninangiotensin system and potassium are the major regulators.55 Electrolytes Potassium is important for the stimulation of aldosterone secretion.56 It has been suggested that potassium rather than the renin-angiotensin system stimulates aldosterone secretion during salt restriction.57 However, Jorde et al32 noted no correlation between plasma aldosterone concentration and serum potassium concentration in patients with chronic heart failure during relatively long-term ACE inhibitor therapy. Reports to date have shown no changes in urinary electrolyte (sodium/potassium excretion) or serum potassium concentration, even when the plasma aldosterone concentration decreases after ACE inhibitor therapy.40,42,44 In our study in patients with essential hypertension or diabetic nephropathy, we observed no significant differences in electrolytes on aldosterone breakthrough.17,24 Nevertheless, small changes in serum potassium concentration within the physiologic range affect aldosterone secretion.58 Thus, potassium levels would always be relevant and exerting an effect on aldosterone, whether correlations are found or not. Genetics When Cicoria et al59 administered an ACE inhibitor to 132 patients with chronic heart failure for more than 6 months, they noted aldosterone breakthrough in 10% of the patients. These patients with aldosterone breakthrough had a significantly higher rate of the DD genotype in the gene coding for ACE. Given that the ACE D allele is reported to be associated with higher circulating levels of ACE than the I allele,60 it is possible that some genetic determination could explain the mechanism of aldosterone breakthrough. In the various studies performed to date, the percentage of patients with aldosterone breakthrough seems to be consistent, regardless of underlying disease, also suggesting that some genetic predisposition may be involved in aldosterone breakthrough.

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Endothelin-1 In patients with chronic heart failure, the plasma endothelin-1 (ET-1) concentration is elevated,61 and progression of heart failure can be prevented by blockade of ET-1.62 Plasma ET-1 concentrations decrease with short-term ACE inhibitor therapy,63 but have rarely been reported after long-term ACE inhibition. Aldosterone in combination with a high salt diet induces experimental cardiovascular fibrosis in rats, with such fibrosis prevented by a selective ET-A receptor blocker,64 indicating possible interaction between ET-1 and aldosterone. Oshima et al65 recently determined in rat neonatal cardiomyocytes that aldosterone amplifies the effect of ET-1 in inducing cardiac hypertrophy through the activation of c-Jun N-terminal kinase (JNK) pathway. Although we have no evidence to date of the involvement of ET-1 in aldosterone breakthrough, there are clear indications that ET-1 may be involved in the pathophysiologic actions of aldosterone after breakthrough.

Perspective Many large-scale clinical trials have shown that ACE inhibitors have clear hypotensive and organ protective effects. Aldosterone breakthrough, however, has emerged as a major problem in terms of the long-term protection afforded by ACE inhibitors. The RALES trial showed the significance of aldosterone breakthrough and the effectiveness of additional administration of an aldosterone blocker in patients with chronic heart failure. Given the wide range of indications for ACE inhibitors, further studies should be designed to determine in what diseases and for which patients an aldosterone blocker will be indicated. The mechanisms of aldosterone breakthrough remain obscure at the present time, requiring further studies, including those on regional nonepithelial effects of aldosterone.

Acknowledgment We thank Professor John W. Funder (Prince Henry’s Institute of Medical Research, Clayton, Australia) for critical reading of the manuscript.

References 1.

2.

3.

The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429 –1435. The SOLVD Investigators: Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. Pfeffer MA, Brauwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, on behalf of the SAVE investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction; results of the survival and ventricular enlargement trial. N Engl J Med 1992;327:669 – 677.

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4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P, for The Angiotensin-ConvertingEnzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334:939 –945. Heart outcome prevention evaluation (HOPE) study investigators: Effect of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253–259. John Sutton MSt, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E, for the SAVE Investigators: Cardiovascular death and left ventricular remodeling two years after myocardial infarction. Baseline predictors and impact of long-term use of captopril: Information from the Survival and Ventricular Enlargement (SAVE) Trial. Circulation 1997;96:3294 –3299. Swedberg K, Kjekshus J, Snapinn S, for the CONSENSUS investigators: Long-term survival in severe heart failure in patients treated with enalapril. Ten year follow-up of CONSENSUS 1. Eur Heart J 1999;20:136 –139. Shiigai T, Shichiri M: Late escape from the antiproteinuric effect of ACE inhibitors in nondiabetic renal disease. Am J Kidney Dis 2001;37:477–483. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for the Randomized Aldactone Evaluation Study: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 –717. Pitt B: “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995;9:145–149. Struthers AD: Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail 1996; 2:47–54. Hatakeyama H, Miyamori I, Fujita T, Takeda Y, Takeda R, Yamamoto H: Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem 1994;269:24316 –24320. Mizuno Y, Yoshimura M, Yasue H, Sakamoto T, Ogawa H, Kugiyama K, Harada E, Nakayama M, Nakayama S, Ito T, Saito Y, Nakao K: Aldosterone production is activated in the failing ventricles in humans. Circulation 2001;103:72–77. Young M, Funder JW: Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system. J Hypertens 2002;20:1465–1468. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A: Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 1981;91:457–465. Lijnen P, Staessen J, Fagard R, Amery A: Increase in plasma aldosterone during prolonged captopril treatment. Am J Cardiol 1982;49:1561–1563. Sato A, Saruta T: Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001;29:13–21. MacFadyen RJ, Lee AFC, Morton JJ, Pringle SD, Struthers AD: How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 1999;82:57–61. Roig E, Perez-Villa F, Morales M, Jimenez W, Orus J, Heras M, Sanz G: Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J 2000;21:53–57. Tang WHW, Vagelos RH, Yee YG, Benedict CR, Willson K, Liss CL, LaBelle P, Fowler MB: Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002;39:70 –78. Borghi C, Boschi S, Ambrosioni E, Melandri G, Branzi A, Magnani

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22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

787

B: Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol 1993;33:40 –45. Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D, Bittman R, Kleiman J: The EPHESUS Trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Cardiovasc Drugs Ther 2001;15:79 –87. Silvestre JS, Heymes C, Oubenaissa A, Robert V, Aupetit-Faisant S, Carayon A, Swynghedauw B, Delcayre C: Activation of cardiac aldosterone production in rat myocardial infarction. Effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 1999;99:2694 –2701. Sato A, Hayashi K, Naruse M, Saruta T: Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003;41:64 –68. Young M, Head G, Funder J: Determinants of cardiac fibrosis in experimental hypermineralocorticoid states. Am J Physiol 1995; 269:E657–E662. Rocha R, Rudolph AE, Frierdich G, Nachowiak DA, Kekec BK, Blomme EAG, McMahon EG, Delyani JA: Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol 2002;283:H1802–1810. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L, for the CONSENSUS Trial Study Group: Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990;82:1730 –1736. Biollaz J, Brunner HR, Gavras I, Waeber B, Gravras H: Antihypertensive therapy with MK421: angiotensin II–renin relationship to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol 1982;4:966 –972. Cicoira M, Zanolla L, Franceschini L, Rossi A, Golia G, Zeni P, Caruso B, Zardini P: Relation of aldosterone “escape” despite angiotensin-converting enzyme inhibitor administration to impaired exercise capacity in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 89:403–407. Farquharson CAJ, Struthers AD: Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure. J Am Coll Cardiol 2002;39:767–775. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A: Angiotensin II-forming pathway in normal and failing human hearts. Circ Res 1990;66:883–890. Jorde UP, Vittorio T, Katz SD, Colombo PC, Latif F, Le Jemtel TH: Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation 2002;106:1055–1057. Sato A, Suzuki Y, Shibata H, Saruta T: Plasma aldosterone concentrations are not related to the degree of angiotensin-converting enzyme inhibition in essential hypertensive patients. Hypertens Res 2000;23:25–31. Studer R, Reinecke H, Muller B, Holtz J, Just H, Drexler H: Increases angiotensin-I converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerase chain reaction. J Clin Invest 1994;94:301–310. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF, on behalf of the ATLAS Study Group: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999; 100:2312–2318. Retrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JMC, McMurray JJV: Angiotensin converting enzyme (ACE) and nonACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol 2001;37:1056 –1061.

788

ALDOSTERONE AND ACE INHIBITORS

37. Urata H, Ganten D: Cardiac angiotensin II formation: the angiotensin-I enzyme and human chymase. Eur Heart J 1993;14(Suppl 1):177–182. 38. Katugampola SD, Davenport AP: Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart. Clin Sci 2002;102:15–21. 39. Bravo EL, Tarazi RC: Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1979;1:39 –46. 40. Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN: Interruption of the rennin-angiotensin system in hypertensive patients by captopril induces sustained reduction in aldosterone secretion, potassium retention and natriuresis. Hypertension 1979;1:274 –280. 41. Gavaras HG, Brunner HR, Turini GA, Kershaw GR, Tifft CP, Cuttelod S, Gavras I, Vukovich RA, McKinstry DN: Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ14225 in man. N Engl J Med 1978;298:991–995. 42. Johns DW, Baker KM, Ayers CR, Vaughan ED Jr, Carey RM, Peach MJ, Yancey MR, Ortt EM, Williams SC: Acute and chronic effect of captopril in hypertensive patients. Hypertension 1980;2: 565–575. 43. Cleland JGF, Dardie HJ, Hodsman GP, Ball SG, Robertson JIS, Morton JJ, East BW, Robertson I, Murray GD, Gillen G: Captopril in heart failure. A double blind controlled trial. Br Heart J 1984;52: 530 –535. 44. Lijnen P, Fagard R, Staessen J, Verschueren LJ, Amery A: Dose response in captopril therapy of hypertension. Clin Pharmacol Ther 1980;28:310 –315. 45. Sassano P, Chatellier G, Billaud E, Alhenc-Gelas F, Corvol P, Menard J: Treatment of mild to moderate hypertension with or without the converting enzyme inhibitor enalapril. Am J Med 1987; 83:227–235. 46. Rousseau MDF, Konstam A, Benedict CR, Donckier J, Galanti L, Melin J, Kinan D, Ahn S, Ketelslegers JM, Pouleur H: Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor. Am J Cardiol 1994;73:448 –493. 47. Mento PF, Wilkers BM: Plasma angiotensin and blood pressure during converting enzyme inhibition. Hypertension 1987;9 (Part 2):II42–II48. 48. Grossman E, Peleg E, Carroll J, Shamiss A, Resenthal T: Hemodynamic and humoral effects of the angiotensin II antagonist losartan in essential hypertension. Am J Hypertens 1994;7:1041–1044. 49. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Roulean J, Latini R, Maggioni A, Young J, Pogne J: Comparison of candesartan, enalapril, and their combination in congestive heart failure. Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study: The RESOLVD Pilot Study Investigators. Circulation 1999;100: 1056 –1064. 50. Naruse M, Tanabe A, Sato A, Takagi S, Tsuchiya K, Imaki T, Takano K: Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 2002;40:28 –33.

AJH–September 2003–VOL. 16, NO. 9, Part 1

51. Kurtz A, Wanger C: Regulation of renin secretion by angiotensin II-AT1 receptors. J Am Soc Nephrol 1999;10(Suppl 11):S162– S168. 52. Newton MA, Laragh JH: Effect of corticotropin on aldosterone excretion and plasma rennin. J Clin Endocrinol 1968;28:1006 – 1013. 53. Michelakis AM, Horton R: The relationship between plasma renin and aldosterone in normal man. Circ Res 1970;16 –17(Suppl I):185– 194. 54. Conaglen JV, Donald RA, Espiner EA, Livesey JH, Nicholls MG: The effect of ovine corticotropin-releasing factor on catecholamine, vasopressin, and aldosterone secretion in normal man. J Clin Endocrinol Metab 1984;58:463–466. 55. Orth DN, Kovacs WJ, DeBold CR: The adrenal cortex. Regulation of mineralocorticoid secretion, in Wilson JD, Foster DW (eds): Williams’ Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, pp 505–507. 56. Young DB: Analysis of long-term potassium regulation. Endocrine Rev 1985;6:24 –44. 57. Okubo S, Niimura F, Nishimura, Takemoto F, Fogo A, Matsusaka T, Ichikawa I: Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 1999;99:855– 860. 58. Aguilera G, Catt KJ: Loci of action of regulators of aldosterone biosynthesis in isolated glomerular cells. Endocrinology 1979;104: 1046 –1052. 59. Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Cabrini G, Bonizzato A, Graziani M, Anker SD, Coats AJS, Zardini P: Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol 2001;37:1808 –1812. 60. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F: An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;856:1343–1346. 61. McMurray JJ, Ray SG, Abdullal I, Dargie HJ, Morton JJ: Plasma endothelin in chronic heart failure. Circulation 1992;85:1374 –1379. 62. Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F, Compagnon P, Mace B, Comoy E, Letac B, Thuillez C: Role of endogenous endothelin in chronic heart failure. Effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 1997;96:1976 – 1982. 63. Davidson NC, Coutie WJ, Webb DJ, Struthers AD: Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. Heart 1996;75:576 –581. 64. Park JB, Schiffrin EL: Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1. Am J Hypertens 2002;15:164 –169. 65. Oshima Y, Fujio Y, Funamoto M, Negoro S, Izumi M, Nakaoka Y, Hirota H, Yamauchi-Takihara K, Kawase I: Aldosterone augments endothelin-1-induced cardiac myocyte hypertrophy with the reinforcement of the JNK pathway. FEBS Let 2002;31:123–126.