European Journal of Heart Failure

European Journal of Heart Failure 2004 6(5):539-545; doi:10.1016/j.ejheart.2004.04.013

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© 2004 European Society of Cardiology

The clinical implications of aldosterone escape in congestive heart failure

Allan D. Struthers^*

Division of Medicine and Therapeutics, Ninewells Hospital and Medical School Dundee DD1 9SY, UK

^* Tel.: +44-1382-632574; Fax: +44-1382-644972. E-mail address: a.d.struthers{at}dundee.ac.uk

	Abstract

Top Abstract 1. Introduction 2. The characteristics of... 3. Clinical impact of... 4. Pathophysiological effects of... 5. Traditional effects of... 6. Newly discovered effects... 7. The clinical evidence... 8. Conclusion References

 
Angiotensin converting enzyme (ACE) inhibitor therapy does not reliably suppress aldosterone production, and ‘aldosterone escape’ occurs in up to 40% of patients with congestive heart failure (CHF). Aldosterone levels correlate with the risk of cardiovascular events. Aldosterone adversely affects the risk of cardiovascular events via mineralocorticoid receptors in the heart, blood vessels and other sites. Notably, aldosterone contributes to endothelial dysfunction and attenuates endothelium-dependent vasodilatation, at least partly by reducing nitric oxide bioavailability. Aldosterone also promotes myocardial fibrosis and cardiac remodelling by enhancing collagen synthesis, resulting in increased myocardial stiffness and increased left ventricular mass. These mechanisms mediated by aldosterone contribute to increased risk of ventricular arrhythmias and sudden cardiac death. Two major prospective trials, including one in which patients routinely received ACE inhibitor and beta blocker therapy, have shown that the use of an aldosterone blocker significantly reduces all-cause mortality, sudden cardiovascular death and hospitalisation in patients with acute or chronic left ventricular dysfunction or CHF. Inhibition of aldosterone's effect on mineralocorticoid receptors should now be considered standard therapy in these patient populations.

Key Words: Abbreviations • ACE, angiotensin converting enzyme • CHF, congestive heart failure • LMMA, N^G-monomethyl-L-arginine • LVH, left ventricular hypertrophy • NO, nitric oxide • PICP, procollagen type 1 carboxy-terminal peptide • PINP, procollagen type I amino-terminal peptide • PIIINP, procollagen type III amino-terminal peptide • RAAS, renin–angiotensin–aldosterone system • RR, relative risk

Received November 14, 2003; Revised April 4, 2004; Accepted April 20, 2004

	1. Introduction

Top Abstract 1. Introduction 2. The characteristics of... 3. Clinical impact of... 4. Pathophysiological effects of... 5. Traditional effects of... 6. Newly discovered effects... 7. The clinical evidence... 8. Conclusion References

 
The pivotal role of aldosterone in the pathogenesis of congestive heart failure (CHF) has long been recognised. Plasma aldosterone levels can be up to 20-fold higher in untreated patients with CHF compared to normal controls [1], due to pronounced activation of the renin–angiotensin–aldosterone system (RAAS) and reduced hepatic clearance of the neurohormone. Mean aldosterone level is known to correlate significantly with mortality in CHF [1].

However, with ACE inhibitor therapy now given routinely for congestive heart failure, the clinical importance of aldosterone had previously been overlooked because ACE inhibitor therapy was widely believed to suppress aldosterone production effectively by ‘upstream’ RAAS blockade. Increasingly, however, it is becoming evident that following an acute fall in aldosterone in response to administration of an ACE inhibitor, the level of aldosterone rises again, and indeed returns to baseline in some patients, a phenomenon known as ‘aldosterone escape’.

	2. The characteristics of aldosterone ‘escape’

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Aldosterone concentrations >144 pg/ml have been reported in up to 40% of patients with symptomatic CHF [2] despite use of an ACE inhibitor, and in 50% of those with left ventricular hypertrophy (LVH) [3]. In one study, 14 patients with CHF showed only a mean fall of 20% in plasma aldosterone levels after 6 weeks’ treatment with captopril [4]. Aldosterone levels have also been shown to increase progressively in patients given an ACE inhibitor following acute myocardial infarction [5] or for essential hypertension [6].

Even when an ACE inhibitor is given in combination with an angiotensin I receptor antagonist, aldosterone levels remain uncontrolled. In the RESOLVD Pilot Study [7], patients with CHF given both enalapril and candesartan had a significant fall in aldosterone levels at 17 weeks compared to those given either agent alone (P<0.01), but mean aldosterone level had returned to baseline by 43 weeks even with maximum doses of both agents.

Moreover, the extent to which aldosterone escape occurs is highly variable. Among CHF patients treated with captopril for 6 weeks, aldosterone level ranged from 56 to 1568 pmol/l [4].

High plasma levels of aldosterone are more common than high plasma levels of angiotensin II during chronic ACE inhibitor therapy in chronic heart failure [2], and aldosterone levels in patients with CHF can rise independently of an increase in angiotensin II [5,8]. The correlation between levels of the two neurohormones is relatively weak (r=0.6) in patients receiving an ACE inhibitor [1,8]. Interestingly, the absolute level of plasma aldosterone may not be all that matters here, since in experimental animals aldosterone-induced tissue damage only occurs in the coincidental presence of a high sodium diet [9].

The precise mechanism by which aldosterone levels rise during ACE therapy is unclear, but levels of angiotensin II (a potent stimulus for aldosterone production in the adrenal glands) are known to increase over time in patients receiving an ACE inhibitor [2,10]. However, aldosterone escape has been reported in patients without angiotensin II reactivation [8] so this trigger cannot be solely accountable. Another possibility is that ACE inhibitors increase potassium, and potassium is a powerful secretagogue for aldosterone and thus may be a major reason for aldosterone escape. Other aldosterone secretagogues, like ACTH, may also play a role. Alternative pathways may also contribute to rising aldosterone levels, for example the enzyme chymase generates angiotensin II from angiotensin I by a non-ACE pathway in the brain heart and blood vessels [11]. Data from animal studies have shown convincingly that these tissues are enzymatically equipped to produce aldosterone [12], in addition to having mineralocorticoid receptors.

Additionally, there is evidence that aldosterone escape in turn might promote release of angiotensin II, via a positive feedback loop that stimulates ACE in the vasculature [13]. This, and the progressive escape of aldosterone, are thought to contribute to ‘ACE inhibitor resistance’, whereby the effect of ACE inhibitors become blunted and beneficial effects on mortality in CHF decrease over time [14,15].

	3. Clinical impact of aldosterone escape

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The relationship between aldosterone levels and clinical outcomes has been assessed in a neurohormonal substudy of the SAVE trial [16]. Among 534 survivors of myocardial infarction who were randomised to captopril or placebo, mean aldosterone levels were lower among patients who remained free of cardiovascular events over 2 years compared to those who died, developed severe heart failure or experienced a further myocardial infarction. Multivariate analysis showed that aldosterone level significantly correlated to risk of a cardiovascular event (P<0.001). It has also been reported that aldosterone escape is associated with reduced exercise capacity in patients with CHF [17] and decreased compliance of the aorta and its major branches [18], despite administration of ACE inhibitor therapy.

	4. Pathophysiological effects of aldosterone in congestive heart failure

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Aldosterone adversely affects the progression of left ventricular hypertrophy and CHF through a remarkably wide range of pathophysiological mechanisms. Historically, aldosterone was thought to exert its effects solely through mineralocorticoid receptors located on polarized epithelial tissue in the kidney. More recently, however, mineralocorticoid receptors have been detected in a range of non-renal tissues including the brain, blood vessels and the heart, suggesting a more widespread pattern of biological activity.

	5. Traditional effects of aldosterone

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In congestive heart failure, overactivation of the RAAS system and consequent elevation of aldosterone levels leads to excessive sodium retention with expansion of the extracellular volume, resulting in worsening of hemodynamic responsiveness and a fall in cardiac output. This contributes to the vicious cycle whereby decreased renal blood flow stimulates the RAAS further, causing secondary hyperaldosteroidism and further sodium retention. By contributing to electrolyte imbalances, particularly hypokalemia and hypomagnesemia, aldosterone increases the sensitivity of cardiac tissue to arrhythmias with consequent increased risk of sudden death [19,20].

	6. Newly discovered effects of aldosterone in LVH/CHF

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An intense research effort has revealed a host of new pathophysiologic mechanisms associated with aldosterone that could be expected to contribute to the progression of congestive heart failure and sudden cardiovascular death (Fig. 1).

View larger version (8K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Mechanisms whereby aldosterone promotes sudden cardiac deaths.

 
6.1. Endothelial dysfunction
The endothelium plays a critical role in regulation of vascular tone, platelet aggregation, adhesion of leukoctyes and the thrombotic cascade, and endothelial dysfunction is predictive of subsequent cardiovascular events [21]. A growing body of evidence suggests that aldosterone may contribute to endothelial dysfunction.

A randomised crossover study in healthy volunteers has evaluated the effect of acute intravenous aldosterone on peripheral arterial vascular function, as measured by venous occlusion plethysmography [22]. Aldosterone significantly attenuated endothelium-dependent vasodilatation in response to acetylcholine, an endothelium-dependent vasodilator. The maximum vasodilatation was 357±38% with placebo vs. 257±21% in the presence of aldosterone (P<0.05) (Fig. 2), suggesting that aldosterone-induced vasculopathy may play a part in the adverse effect of aldosterone in CHF.

View larger version (14K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Endothelium-dependent vasodilatation in 16 healthy volunteers receiving acetylcholine, randomized to receive acute intravenous aldosterone infusion or placebo. Peripheral arterial vascular function was measured by occlusion plethysmography [22].

 
One mechanism by which aldosterone may induce endothelial dysfunction is through reduction of nitric oxide (NO) bioavailability. Aldosterone has been shown to reduce NO bioactivity in an in vitro study of rat smooth muscle [23]. At the pre-clinical level, a study in rats with experimental CHF has demonstrated that acetylcholine-induced NO-dependent vasodilatation in aortic rings was significantly lower than in control animals [24]. Treatment with the ACE inhibitor trandolapril improved NO-mediated vasodilatation, but addition of spironolactone entirely restored relaxation to the level of controls (Fig. 3).

View larger version (14K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Maximal acetylcholine-induced vasodilatation of aortic rings in rats with experimental CHF following administration of the ACE inhibitor trandolapril with or without spironolactone, compared to controls [24].

 
Clinically, a double-blind, randomised study conducted in patients with chronic heart failure receiving ACE inhibitor therapy has shown that aldosterone blockade by spironolactone increases NO bioactivity compared to placebo [13]. In this trial, infusion of the NO synthase inhibitor L-NMMA resulted in significantly greater vasoconstriction in spironolactone-treated patients compared to those in the placebo group, indicating that basal NO bioactivity is improved by aldosterone blockade. In the same study, spironolactone was also associated with a significant increase in forearm blood flow in response to acetylcholine, but had no effect on blood flow in response to sodium nitroprusside, an endothelium-independent vasodilator (Fig. 4). These are exactly the findings one expects to see when a treatment (aldosterone blockade) improves endothelial function by increasing vascular NO bioactivity.

View larger version (9K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Forearm blood flow (FBF) among 10 patients with NYHA class II–III chronic heart failure receiving treatment with diuretics and an ACE inhibitor during a randomized, double-blind crossover study of 50 mg/day spironolactone ()vs. placebo () in response to acetylcholine, N-monomethyl-L-arginine (L-NMNA) and sodium nitroprusside (control vasodilator). Values are mean±S.E.; *P<0.05; **P<0.001 for differences between treatments [13]. Reproduced with permission from: Farquharson CAJ and Struthers AD. Spironalactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000;101:594–597.

 
Aldosterone may also stimulate development of a vascular inflammatory response in many tissues including cardiac tissue. Aldosterone also increases cytokine activity such as osteopontin, cyclooxygenase-2 and macrophage chemoattractants [25]. There is also early evidence from a rabbit model of atherosclerosis that the selective aldosterone blocker eplerenone reduces the generation of oxygen free radicals [26], and this may be why it increases NO bioactivity, since oxygen free radicals such as the superoxide anion normally serve to inactivate NO.

6.2. Myocardial fibrosis and cardiac remodelling
Aldosterone also contributes to the progression of heart failure by promoting perivascular and interstitial myocardial fibrosis, acting via mineralocorticoid receptors located in the heart. This reduces the flexibility of myocardial tissue such that it requires a higher filling pressure and increases the likelihood of diastolic dysfunction. Structural remodelling of the interstitial collagen matrix, producing patchy myocardial fibrosis would also be expected to result in electrical inhomogeneity and be an arrhythmogenic influence. Such arrhythmogenicity may be further potentiated by the potassium and magnesium depletion induced by aldosterone. Patients with New York Heart Association Grade II–III randomised to the aldosterone blocker spironolactone had a significant reduction in ventricular arrhythmias on 24-h ambulatory electrocardiography compared to those receiving placebo (P<0.05) [27].

The pro-fibrotic effect of aldosterone has been demonstrated at a cellular level, pre-clinically, and in several clinical settings. In vitro experiments have reported that administration of aldosterone to cardiac fibroblasts significantly enhances collagen synthesis [28], a finding that has been borne out in rat models [29]. At the preclinical level, histological examination of tissue from uninephrectomized rats given 0.9% salt water for 4 weeks revealed extensive cardiac and perivascular fibrosis that was markedly reduced in rats treated with the selective aldosterone blocker eplerenone [30]. In a dog model of heart failure, 3 months’ treatment with eplerenone was found to reverse the increase in end-diastolic volume and end-systolic volume seen in untreated animals, and reduced cardiomyocyte cross-sectional area by 28%, indicating attenuation of left ventricular remodelling with aldosterone blockade [31].

The first proof that aldosterone promotes myocardial fibrosis in man came when it was shown that spironolactone reduced plasma level of PIIINP in heart failure [32]. PIIINP is procollagen type III amino terminal peptide and is an indirect marker of myocardial collagen turnover in man. Clinically, a comparison of patients with essential hypertension revealed that those with hyperaldosteronism had a higher left ventricular mass index (53.7 vs. 45.5 g/m²) than those with normal aldosterone levels, together with alterations in myocardial texture that suggested increased collagen deposition [33]. In a study of 46 patients experiencing their first myocardial infarction who were treated with an ACE inhibitor and randomised to placebo or the aldosterone inhibitor potassium canrenoate, type III procollagen (a precursor of the cardiac extracellular matrix constituent type III fibrillar collagen) was significantly higher in the placebo group at all time-points during the 1-year study. At 6 months and 1 year, left ventricular volume was significantly smaller in the treatment group [34]. A further study, undertaken in patients with essential hypertension who were treated with ACE inhibitor therapy, has reported that left ventricular mass index fell significantly among patients in whom aldosterone level was controlled, but remained unchanged in those with aldosterone escape [3]. Notably, a beneficial effect of spironolactone on left ventricular mass index has been reported in patients with essential hypertension receiving an ACE inhibitor [35].

The adverse effects of aldosterone on endothelial function may account partially for its pro-fibrotic action. Endothelial dysfunction could lead to microthrombi, tissue microinfarction and injury, which repairs itself as fibrosis. Whether aldosterone produces fibrosis directly or whether it acts via a vasculopathy-induced injury of tissues is an intriguing and as yet unanswered question, but time sequence studies suggest the latter. Another possible contributor to aldosterone's pro-fibrotic effect is that aldosterone may have immunostimulant properties leading to inflammation, tissue injury and repair fibrosis [36].

6.3. Decreased baroreceptor sensitivity
Another potentially harmful effect of aldosterone is its ability to blunt the baroreflex response. Perfusing the carotid sinus directly with aldosterone has been shown to reduce maximum baroreceptor discharge [37], while in dogs chronic administration of aldosterone elevates the threshold for baroreflex activation and decreased peak discharge rate [38]. The first demonstration of such an effect in man came when it was shown that aldosterone inhibits baroreflex sensitivity in healthy volunteers (8.36±2.19 ms/mmHg vs. 10.12±2.27 ms/mmHg, P<0.04) [39], an effect that occurs independent of the attenuation of baroreflex control of heart rate and sympathetic activity associated with angiotensin II.

	7. The clinical evidence for aldosterone blockade

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The wealth of data indicating a pathogenic role of aldosterone in CHF has now been validated by two major prospective trials. In the RALES study, 1663 patients with severe CHF (New York Heart Association class III–IV) were randomised to receive spironolactone or placebo [40]. Patients received an ACE inhibitor if tolerated (94% in the placebo group, 95% in the spironolactone cohort) and a loop diuretic, and three-quarters were also given digitalis. However, only approximately 10% were receiving beta blocker therapy. The trial was discontinued early because after a mean follow-up of 24 months, the relative risk (RR) of death was 0.70 (95% CI 0.6–0.82, P<0.001) among patients receiving spironolactone, i.e. a 30% reduction in risk of death with aldosterone blockade. This reduction in mortality was largely accounted for by a significant fall in deaths due both to progression of heart failure (RR 0.64, 95% CI 0.51–0.80, P<0.001) and sudden cardiovascular death (RR 0.71, 95% CI 0.54–0.95, P=0.02). The spironolactone-treated patients had a significant improvement in symptoms of heart failure according to NYHA classification (P<0.001). However, gynecomastia or breast pain occurred more often in men receiving spironolactone (10%) than placebo (1%, P<0.001) due the drug's affinity for androgen receptors.

The dose of spironolactone used in the RALES study (25–50 mg/day) has no apparent diuretic effect, as judged by a substudy where the sodium retention score was measured. The authors concluded that a cardioprotective effect of aldosterone blockade contributed to the reduction in mortality rate.

The reduction in sudden cardiovascular death seen with spironolactone treatment came initially as a surprise to non-experts, but clearly there are many possible mechanisms for this, ranging from aldosterone worsening endothelial function and so increasing coronary events, to it having arrhythmogenic effects by promoting myocardial fibrosis and depleting potassium and magnesium [27]. A subgroup of the RALES study population were analysed for serological markers of cardiac collagen turnover (PICP, PINP and PIIINP), to monitor the extent of cardiac tissue repair and fibrosis [41]. The procollagen markers decreased in the spironolactone group over the 6 months from baseline, but remained unchanged in the placebo cohort, indicating that the benefit of aldosterone blockade paralleled the reduction of cardiac fibrosis. Interestingly, serum levels of all three markers were independently associated with increased risk of death, and the beneficial effects of spironolactone on patient survival were predominately seen among patients with the highest baseline levels of collagen markers. It is not yet clear whether aldosterone blockade is more effective or not in CHF patients with higher plasma levels of aldosterone. In recent hypertension studies, aldosterone blockade appears to reduce BP in all patients irrespective of their renin status. There could be many explanations for this but one is that the mineralocorticoid receptor can be occupied and activated by cortisol as well as by aldosterone. In this case, blocking the receptor could be beneficial irrespective of whether the receptor is being stimulated by aldosterone or cortisol.

More recently, the EPHESUS trial has evaluated use of the selective aldosterone blocker eplerenone in 6632 patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure [42]. Severity of CHF was less pronounced than in the RALES study, with mean left ventricular ejection fraction of 33% compared to 25% in the RALES population. Pharmacotherapy also differed: most notably, 75% of patients received beta blockers vs. approximately 10% of those in RALES. During a mean follow-up of 16 months, patients randomised to eplerenone had a 15% reduction in mortality compared to patients on placebo (RR 0.85, 95% CI 0.75–0.96, P=0.008), and risk of hospitalisation for heart failure also fell by 15% (RR 0.85, 95% CI 0.74–0.99, P=0.03). Similar to the RALES study, the reduction in death from cardiovascular causes was largely accounted for by a 21% fall in sudden death (201 deaths in the eplerenone group vs. 162 in those receiving placebo, RR 0.79, 95% CI 0.64–0.97, P=0.03). This indicates that the myocardial protective effect of aldosterone blockade is maintained even in the presence of optimal therapy and in patients close to the acute phase of myocardial infarction. Incidence of gynecomastia and impotence did not differ between the eplerenone and placebo groups, due to the low affinity of eplerenone for androgen receptors. There was the expected small increase in hyperkalaemia (+1.6%) with eplerenone, but this was balanced by a bigger reduction in hypokalaemia (–4.7%). Eplerenone is metabolised by CYP3A4 and data are awaited on whether potent inhibitors of this enzyme such as ketoconazole, fluconazole or erythromycin interact pharmacokinetically with eplerenone.

	8. Conclusion

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Aldosterone escape is common in CHF patients despite use of ACE inhibitor or angiotensin I receptor blockade. Since the relationship between levels of angiotensin II and aldosterone is not close, and since the pathophysiological consequences of aldosterone are influenced by sodium, the identification of patients at risk from excessive aldosterone is not straightforward and all patients with CHF should be considered at risk from aldosterone.

In addition to the traditional effects of aldosterone on fluid and sodium retention, a range of newly-recognised effects of aldosterone contribute to its detrimental effect on risk of cardiovascular events, in particular sudden death. Apart from the well-recognised effect of potassium and magnesium depletion, pre-clinical and clinical studies have shown that aldosterone promotes endothelial function and cardiac fibrosis, actions which would be expected to play an important part in promoting cardiac events.

We now have convincing clinical evidence that these effects translate to a significantly harmful effect of aldosterone in patients with CHF. Large-scale prospective studies have reported a marked and significant benefit from use of an aldosterone blocker in terms of overall mortality, cardiovascular mortality (particularly sudden death) and hospitalisation. In one trial, these improvements were seen even when patients with less severe CHF were already taking an ACE inhibitor and a beta blocker in addition to aldosterone blockade. Optimal therapy for patients with congestive heart failure should now routinely include an aldosterone blocker since two major trials clearly documented a reduction in total mortality by doing so.

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