Aldosterone-induced cardiac damage: focus on blood pressure independent effects

AJH

2003; 16:80 – 86

Review

Aldosterone-Induced Cardiac Damage: Focus on Blood Pressure Independent Effects Bernhard M.W. Schmidt and Roland E. Schmieder Mineralocorticoid receptor (MR) antagonists have been used as potassium-sparing diuretics in hypertension. However, in addition to their diuretic and secondary blood pressure (BP)-lowering effects, there exists strong evidence from clinical and experimental studies that they prevent aldosterone-induced myocardial fibrosis independent of their effect on BP. Sustained elevation of aldosterone levels and increased sodium intake in animal models has been found to induce myocardial fibrosis. Fibrosis of the right ventricle, the atria, and the pulmonary artery supports the concept that these effects are BP independent, corroborated by the finding that spironolactone in a dosage not sufficient to lower BP prevents myocardial fibrosis. Patients suffering from primary hyperaldosteronism or Conn’s adenoma show more myocardial fibrosis, as assessed by echocardiography, than essential hypertensive

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o date mineralocorticoid receptor (MR) antagonism has not been widely used as a therapeutic option in treating essential hypertension. In France and Japan a spironolactone-containing combination is the most common antihypertensive drug, in Germany no MR antagonist is approved by federal authorities for first-line treatment of hypertension. Recently, data have been reported that shed new light on the importance of aldosterone in cardiovascular disease. As a consequence interest shifted from the mechanisms leading to high blood pressure (BP) to the pathophysiology of BP-independent organ damage. ● The results of RALES1 in chronic heart failure strongly support the concept of cardioprotection by MR antagonism. The fact that even in patients with normal BP, MR antagonism exerts its positive effects to the heart supports the concept of pressure independent myocardial damage caused by aldosterone. The existence of a local renin angiotensin aldosterone system (RAAS) allowing local production of aldosterone has been proposed and linked to myocardial fibrosis.2 Primary hyperaldosteronism might Received April 1, 2002. First decision May 22, 2002. Accepted September 12, 2002. From the Department of Medicine IV/Nephrology, University of Erlangen-Nu¨rnberg, Germany. The authors’ own work cited in this review was funded by the 0895-7061/03/$30.00 PII S0895-7061(02)03199-0

patients. Several mechanisms have been proposed to mediate the profibrotic effects of aldosterone, including the possibility of local aldosterone production in the heart, an increase of myocardial AT1-receptor density, and enhanced local angiotensin converting enzyme expression. Furthermore, aldosterone increases endothelin receptor expression, which also might cause myocardial fibrosis. Because of the pivotal importance of aldosterone binding to the MR, MR antagonists have emerged as attractive compounds that provide specific end organ protection beyond solely their antihypertensive effects. Am J Hypertens 2003;16:80 – 86 © 2003 American Journal of Hypertension, Ltd. Key Words: Aldosterone, fibrosis, cardiac remodeling, myocardium. be a far more common cause of hypertension than previously believed,3 accounting for up to one-third4 of patients referred to hypertension treatment centers and up to 10% of unselected patients.5 Eplerenone is a new selective MR antagonist, which will be available in the near future. Although other MR antagonists have been shown to be effective in hypertension, the appearance of the new drug, with a superior profile of side effects,6 will intensify discussion of the positive effects of MR antagonism. The importance of aldosterone for the development of renal damage has been recently reviewed.7 We will focus on the BP-independent impact of aldosterone on cardiac damage. Furthermore, the clinical and experimental evidence for cardiac fibrosis induced by aldosterone will be critically reviewed.

Evidence From Clinical Studies Primary Hyperaldosteronism Primary hyperaldosteronism is characterized by elevated aldosterone levels accompanied by suppressed renin and Deutsche Forschungsgemeinschaft (DFG Schm 638/8-1 and 2). Address correspondence and reprint requests to Prof. Dr. Roland E. Schmieder, Universita¨t Erlangen-Nu¨rnberg, Medizinische Klinik IV, Breslauer Strasse 201, 90471 Nu¨rnberg, Germany; e-mail: roland. [email protected] © 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

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FIG. 1. Mean values of the videodensitometric measurement (CVI) in the septum (s), the posterior wall (pw), and the mean (m) of both indexes in patients with primary aldosteronism (PA) and essential hypertension (EH). (Reprinted with permission from Rossi GP, et al: Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension 2002;40:23–27.)10

angiotensin II, thus excluding significant concurrent effects of angiotensin II. Patients with primary hyperaldosteronism8 and Conn’s adenoma9 are characterized by impaired left ventricular diastolic function of the left ventricle suggesting increased fibrosis compared to matched patients with essential hypertension. In patients with Conn’s adenoma these alterations are corrected by adrenalectomy, underlining the causative role of aldosterone.9 In addition, left ventricular texture assessed by videodensitometry of the myocardium has been shown to be altered in primary hyperaldosteronism compared to essential hypertension, also suggesting increased collagen deposition (Fig. 1).10 Therefore, these studies suggest a BP-independent effect of aldosterone on left ventricular structure and function. However, there are no studies available showing myocardial fibrosis in humans by histology of myocardial biopsies or necropsy. Essential Hypertension In essential hypertensives it has been shown that inadequate suppression of aldosterone in response to increased dietary sodium intake is related to impaired midwall fractional fiber shortening, a parameter of systolic function, and increased velocity time integral ratio A/E, a parameter of diastolic function.11 These findings are in line with the results of a second study, in which impairment of diastolic function as assessed by early inflow peak velocity, deceleration of the early filling, and E/A ratio was significantly correlated with plasma aldosterone levels.12 Aldosterone has thus emerged as a determinant of cardiac structural and functional adaptive processes in essential hypertension, independent of its effects on BP. Chronic Heart Failure and Myocardial Infarction The MR antagonism by spironolactone reduced the mortality of patients suffering from severe heart failure by

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about 30% on top of the standard therapy including angiotensin converting enzyme (ACE) inhibitors.1 This effect was at least in part attributed to an antifibrotic effect of MR blockade. In a substudy of Randomized Aldactone Evaluation Study (RALES) markers of extracellular matrix turnover (especially PIIINP [procollagen type III amino-terminal peptide]) were prognostic for mortality and PIIINP serum levels decreased during spironolactone therapy.13 Similarly, the MR antagonist potassium canrenoate decreased serum levels of PIIINP and left ventricular dilation in patients after anterior myocardial infarction, in addition to ACE inhibitor therapy.14 Therefore, there are substantial clinical data linking aldosterone to myocardial remodeling processes, especially myocardial fibrosis. This link seems again to be independent of hemodynamic factors.

Local Aldosterone System in the Heart In the rat myocardium the mineralocorticoid receptor and the enzymes required for aldosterone synthesis have been found,15 suggesting a complete aldosterone system at the tissue level. After myocardial infarction in the rat, aldosterone synthase mRNA and aldosterone levels were reported to be increased in the noninfarcted myocardium.16 This increase of local aldosterone levels is prevented by angiotensin II receptor antagonists, suggesting that cardiac aldosterone production is at least in part regulated by angiotensin II. Takeda et al17 showed an increase of intracardiac and a decrease of systemic aldosterone levels after increasing the sodium load in normotensive WistarKyoto rats. These data suggest a disparate regulation of aldosterone production in the myocardium and in the adrenal gland. The importance of local aldosterone production is, however, questioned by a study by Rocha et al.18 They showed in the N␻-nitro-L-arginine methyl ester (LNAME), angiotensin II/salt model of myocardial damage in rats that MR antagonism and adrenalectomy abolishes the myocardial damage (which in this model is characterized by myocardial necrosis and vascular lesions, but not by myocardial fibrosis) and administration of aldosterone restores it. These data suggest a determining role for adrenal aldosterone production, and the unimportance of the putative myocardial production. Because there is a possibility that local aldosterone production depends on the species and the strain examined, human data are of particular interest.19,20 In humans mineralocorticoid receptors have been detected in the myocardium,21 suggesting that aldosterone may produce biologic effects on the myocardium. To date, however, definitive proof of physiologically relevant aldosterone production in the human heart is lacking. Kayes-Wandover and White22 showed that aldosterone synthase mRNA is not detectable in the normal adult myocardium. Young et al19 confirmed these data and detected expres-

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sion of aldosterone synthase and 11␤-hydroxylase in some failing human hearts. The levels of mRNA for the different enzymes detected in the failing19,22 human heart are 100- to 10,000-fold lower than in the adrenal gland, rendering each of them rate limiting. It thus seems likely that a group of cardiac cells may produce higher levels of enzymes, an issue that has to be clarified by additional studies.23 The human in vivo data on aldosterone production in the heart are conflicting. Diametrically opposite results have been reported in studies using an almost identical study design (ie, comparing aldosterone levels measured in the aortic root and the coronary sinus). One group showed higher aldosterone levels in the coronary sinus in patients with heart failure24 or essential hypertension without systolic dysfunction,25 which they did not observe in controls. This would suggest aldosterone production in the diseased but not the normal human heart. A second group reported decreased aldosterone levels in the coronary sinus in patients with heart failure and in healthy controls suggesting aldosterone extraction by both the diseased and the healthy heart,26 with cardiac extraction lowered by spironolactone therapy. The two sets of data are difficult to reconcile. The amount of aldosterone released from the heart (increase of aldosterone levels by up to 30%24) seems considerable given the levels of enzyme expression, and coronary venous blood flow. It thus remains unresolved whether cardiac production of aldosterone contributes to the circulating pool in relevant amounts: long experience of patients with adrenal insufficiency has clearly shown that they need substitution therapy. In conclusion, despite being an attractive concept it remains controversial whether in humans aldosterone is synthesized in the diseased heart to a pathophysiologic relevant extent.

Aldosterone Effects to the Heart Ionic Movement Aldosterone has been linked to ventricular ectopic activity, especially because of its kaliuretic action. However, in addition there are direct cardiac actions of aldosterone that may cause electrical instability of the myocardium and promote cardiac remodeling. In rabbits, aldosterone enhances the influx of Na⫹ into myocardial cells by inducing the Na⫹-K⫹-2Cl⫺ cotransporter. Activation of the cotransporter increases cellular volume and decreases cardiac compliance, thereby producing a positive inotropic effect and impaired left ventricular filling.27 Using the whole cell patch clamp technique it has been shown that long-term administration of aldosterone decreases the affinity of intracellular Na⫹ for the sarcolemmal Na⫹-K⫹ pump (ie, Na⫹-K⫹-ATPase) without altering the concentration of myocardial Na⫹-K⫹ pump sites.28 Because Na⫹-K⫹ pump inhibition leads to activation of important growth-related genes in myocytes,29 aldosterone

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potentially contributes to cardiac remodeling by this mechanism. Furthermore, activation of the Na⫹-K⫹ pump in fibroblasts is related to fibroblast growth and collagen synthesis.30 Another electrolyte probably linking aldosterone to myocardial ectopic activity is magnesium. Whereas chronic aldosterone excess does not alter plasma magnesium levels,31 it has been shown that intracellular magnesium (iMg2⫹) is decreased in primary aldosteronism. In lymphocytes this has been shown to reflect an increased activity of the Na⫹-Mg⫹ antiporter in the plasma membrane, an effect blocked by MR antagonism.32 Because iMg2⫹ depletion favors ventricular ectopy reversing cellular magnesium depletion might be one factor leading to the increased survival of patients receiving spironolactone in the RALES trial. In addition, potassium and magnesium are major regulators of aldosterone production in the adrenal gland, with potassium increasing33 and magnesium decreasing34 aldosterone production. Finally, aldosterone upregulates Ca2⫹ influx in rat cardiomyocytes also leading to ventricular ectopic activity,35 and increasing intracellular Ca2⫹ in myocardial fibroblasts may lead to the induction of myocardial fibrosis (discussed later).36 Myocardial Fibrosis Brilla and Weber37,38 has shown in the early 1990s that chronic elevation of aldosterone levels and sodium intake induces myocardial fibrosis in the left and right ventricle. The observation that fibrosis takes place even in the right ventricle argues for the concept that the fibrotic processes are BP independent (Fig. 2). Furthermore, in aldosterone/ salt-treated rats fibrosis also occurs in both the left and right atria and the adventitia of the pulmonary artery, confirming that BP and increased wall stress are not necessary for the aldosterone-induced fibrosis.39 This is supported by the observation that infrarenal aortic banding leading to hypertension and increased wall stress without activation of the RAAS causes left ventricular hypertrophy without left or right ventricular fibrosis.40 The latter data also document that myocardial fibrosis is independent of left ventricular hypertrophy. In addition, it has been shown that treatment with small (ie, nondepressor) doses of spironolactone prevents myocardial fibrosis, whereas the aldosterone/salt-induced hypertension is unaltered and myocardial hypertrophy develops. Higher (ie, depressor) doses of spironolactone lowered the BP to control values and prevented left ventricular hypertrophy.41 This clearcut study proves the pressure independence of the aldosterone-induced myocardial fibrosis. Finally, in another study,42 spironolactone prevented myocardial fibrosis in old normotensive rats without causing significant changes in BP. Further evidence of a specific cardiac effect of aldosterone independent of BP comes from a study43 in which

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finding of (reactive) fibrosis without detection of scarring (Fig. 3). Components of Induction of Myocardial Fibrosis By Aldosterone Despite considerable data on the mechanisms of aldosterone-induced myocardial damage and its interaction with other humoral systems, this issue still awaits conclusive answers. Here are some proposed mechanisms.

FIG. 2. Total collagen volume fraction for the left (upper panel) and the right (lower panel) ventricles after 8 weeks of renovascular hypertension (RHT), aldosterone infusion with high (AL) or low (ALLO) sodium diet, RHT or AL with pretreatment followed by low dose spironolactone (RHT ⫹ S and AL ⫹ S) treatment, AL with high dose spironolactone treatment (AL ⫹ SS) and controls. *P ⬍ .005, **P ⬍ .0001 v control; †P ⬍ .005, ††P ⬍ .0001 v RHT or AL. (Reprinted with permission from Brilla CG, Weber KT: Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 1992;26:671– 677.)37

aldosterone was systemically infused in rats in parallel with an intracerebroventricular infusion of the MR antagonist RU28318. In this setting, arterial hypertension was abolished due to blockade of central mineralocorticoid effects, whereas the myocardial changes that occurred were identical to those seen with aldosterone infusion alone. Of note, aldosterone-induced myocardial fibrosis does occur only if sodium intake is elevated; in rats, aldosterone alone does not significantly induce fibrosis.38 The pathophysiologic mechanisms of this interaction are not yet clear. Fibrosis can occur with injury to parenchymal cells (reparative fibrosis), or without such injury (reactive fibrosis). Aldosterone can induce necrosis of cardiomyocytes causing microscopic scarring (ie, reparative fibrosis). However, these effects of aldosterone are mainly mediated by hypokalemia, because microscopic scarring is prevented in uninephrectomized aldosterone/salt-treated rats by the potassium-sparing diuretic amiloride44 or by supplementation with potassium.43 The induction of reactive fibrosis by aldosterone is the more important mechanism for disease states and occurs without severe hypokalemia, in line with the histologic

Renin-Angiotensin-Aldosterone System It has been proposed that aldosterone causes fibrosis by interaction with angiotensin II. Robert et al45 showed in aldosterone salt-treated rats that aldosterone increases AT1 receptor mRNA and the ventricular density of the AT1 receptor. Myocardial fibrosis was almost blunted to the same extent by AT1 receptor antagonists as by spironolactone in this study. Spironolactone decreased the number of AT1 receptors suggesting an action through the MR. On the other hand, other investigators could not demonstrate a relevant reduction in myocardial fibrosis by ACE inhibition46,47 or angiotensin II type 1 receptor blockade in similar animal models. In addition, aldosterone has been reported to increase expression of the angiotensin converting enzyme in cardiomyocytes, as shown in fibrotic tissue of aldosterone/salttreated rats48 and in cultured fetal rat cells.49 In the latter study, however, 10 ␮mol/L aldosterone was used. At this dosage aldosterone acts on the glucocorticoid receptor, which is confirmed by the fact that the effect was reversed by 50% by equimolar spironolactone. Furthermore, at this dose nonspecific membrane effects of aldosterone occur.50 Therefore, it remains to be proven whether aldosterone is able to activate the local production of angiotensin II, which, itself at least in rats, is reported to induce local aldosterone production, and is compatible with a positive feed-back loop within the local RAAS; further studies are clearly required. An important second messenger in the processes leading to aldosterone/salt-induced fibrosis is intracellular Ca2⫹. Both aldosterone and angiotensin II are capable of increasing intracellular calcium. In rats with aldosterone/salt hypertension and in angiotensin II-infused rats the calcium channel blocker mibefradil has been shown to block aldosterone and angiotensin II-induced myocardial fibrosis.36 Endothelin and Bradykinin Beyond the RAAS other hormonal effectors may be involved in aldosterone/saltinduced fibrosis. Endothelin gene expression is increased in deoxycorticosterone acetate (DOCA)-salt treated rats in coronary arteries and the endocardium.51 In addition, aldosterone upregulates endothelin receptors in ventricular fibroblasts.52,53 Conversely, blockade of the endothelin receptors by the nonspecific ETA and ETB receptor blocker bosentan attenuates cardiac fibrosis.54 Furthermore, it has been shown in DOCA-salt treated rats that blockade of the ETA receptor specifically suppresses myo-

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FIG. 3. Sirius red staining in control rats (A) and DOCA-salt rats (B–D) showing no and increasing degrees of myocardial fibrosis.

cardial fibrosis but does not alter myocardial hypertrophy.55 These results await further confirmation. Finally there should soon be indications from studies in human heart failure or hypertension whether endothelin antagonism is beneficial in terms of left ventricular fibrosis and patient survival. Similarly, bradykinin had been proposed to play a role in aldosterone-induced myocardial fibrosis, because in aldosterone/salt-treated rats the concentration of bradykinin receptors is increased,56 and blockade of bradykinin B2 receptors has been shown to reduce myocardial fibrosis.57 However, recent data from bradykinin B2 receptor knockout mice do not support the concept that bradykinin is profibrogenic with regard to the heart, but the opposite. In bradykinin B2 receptor knockout mice cardiac remodeling occurs, suggesting a normally preventive action of bradykinin.58,59 This is in line with results in primary cultures of adult rat cardiac fibroblasts, in which bradykinin reduced the mRNA levels of collagens type I and III and fibronectin.60 In conclusion, for both bradykinin and endothelin more studies are necessary to gauge their importance in aldosterone-induced myocardial fibrosis. Inflammation Perivascular inflammation in the myocardial tissue is a common histologic feature in aldosterone-induced myocardial damage. The collagen-producing fibroblasts have been shown to colocalize with several

kinds of inflammatory cells in animal models of myocardial fibrosis.61 During chronic aldosterone infusion in salttreated rats infiltration by macrophages and lymphocytes occurs after 3 weeks with subsequent fibrotic changes occurring after 4 weeks.62 Thus, the inflammatory response precedes the fibroblast response and is mandatory for the development of fibrosis.63 Cytokines, such as transforming growth factor-␤, platelet-derived growth factor, and interleukins 1 and 6, are released from the inflammatory cells and have the ability to induce fibrotic changes. These interactions have been recently reviewed in detail.63 A recent study using weekly subcutaneous injection of DOCA has shown a very rapid time course of inflammatory and fibrotic changes. Fujisawa et al64 observed an increase in type III collagen deposition 2 days after acute elevation of mineralocorticoid levels, followed by inflammatory changes; these data await confirmation. Cell Proliferation The fibrotic changes following aldosterone infusion are accompanied by fibroblast proliferation.62 Not surprisingly the antiproliferative agent N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) markedly reduced cardiac fibrosis in aldosterone/salt-treated rats, without changing the BP.65 Because Ac-SDKP levels are increased by ACE inhibition, the decrease of fibrotic changes due to ACE inhibition might be at least in part mediated by this pathway.

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Conclusion There is now striking evidence for specific BP-independent aldosterone effects inducing myocardial fibrosis. Although many mechanisms have been suggested to be involved in these effects, there remain questions to be answered: ● Is aldosterone locally produced in the (diseased) adult myocardium in humans? ● How might such aldosterone production in the myocardium be regulated? ● Why is sodium of such importance for the profibrotic effects of aldosterone? ● How can we define patients at increased risk for aldosterone-induced cardiac damage? ● Are aldosterone synthase polymorphisms or aldosterone-to-renin ratio adequate tools to identify those patients who might profit from specific antialdosterone therapy? From a clinical point of view, the most important issue is to clarify which intervention is most effective in blocking the profibrotic processes of aldosterone. Clearly, the MR antagonism is the most logical candidate, and spironolactone has shown its cardioprotective efficacy in the RALES trial. Therefore, the importance of MR antagonism in the therapy of essential hypertension has to be defined as new.

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