Mineralocorticoid antagonism and cardiac hypertrophy

Aldosterone provides circulatory support by promoting reabsorption of sodium in exchange for potassium in the kidney. Mineralocorticoid receptors (MRs) are found in nonepithelial (vessel, heart, and brain) and epithelial tissues. Excess aldosterone may exert harmful effects by provoking hypertrophy and fibrosis in the cardiovascular system, thus contributing to reduced vascular compliance and increased ventricular stiffness. Primary aldosteronism is the most common cause of mineralocorticoid-induced hypertension, and MR antagonism offers the best prospect for achieving therapeutic goals. MR blockade also ameliorates pathological changes in the heart in the setting of low-aldosterone hypertension. The beneficial cardiac effects of MR antagonists are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by activation of MRs. MR antagonism thus may have wide therapeutic potential in various cardiovascular diseases, with its benefit not limited to those characterized by aldosterone or salt excess.     

Effect of Aldosterone and MR Blockade on the Brain and the Kidney

The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-I converting enzyme (ACE) inhibitors and angiotensin II (Ang II) subtype-1 (AT₁) receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur whereby aldosterone levels return to, or exceed, baseline levels. The classical effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, the presence of mineralocorticoid receptors (MR) at nonepithelial sites in the brain, heart and vasculature, is consonant with the fact that aldosterone also has direct effects in these tissues. Substantial evidence now exists that supports the action of aldosterone at non-epithelial sites which in turn provokes a number of deleterious effects on the cardiovascular system including necrosis and fibrosis of the vasculature and the heart, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release and production of cardiac arrhythmias. Several studies have now shown that vascular and target-organ protective effects of MR antagonism occurs in the absence of significant blood pressure lowering or fluid loss, which is consistent with a major role for endogenous mineralocorticoids as direct mediators of cardiovascular injury. Adverse cardiovascular effects may occur in response to aldosterone alone, activation of the RAAS or aldosterone escape during chronic ACE inhibition or AT₁ receptor antagonism. The specific blockade of aldosterone action should prove to be of great therapeutic value in the prevention of cerebral and renal vascular disease and associated end-organ damage.     

Mineralocorticoid Receptors: Distribution and Activation

Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone aldosterone = cortisol), and are found in both Na⁺ transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain). MR evolved before aldosterone synthase, consistent with their acting in nonepithelial tissues as high affinity glucocorticoid receptors, essentially always occupied by normal levels of endogenous glucocorticoids. In epithelial tissues the enzyme 11 hydroxysteroid dehydrogenase Type 2 (11HSD2) allows aldosterone to selectively activate MR, by converting cortisol to cortisone and NAD to NADH. 11HSD2 debulks intracellular cortisol by 90%, to levels 10-fold those of aldosterone, so that when the enzyme is operating most epithelial MR are occupied but not activated by cortisol. When intracellular redox state is changed—by inhibition of 11 HSD2, generation of reactive oxygen species, or intracellular introduction of oxidised glutathione (GSSG)—cortisol changes from an MR antagonist to an MR agonist. This bivalent activity of cortisol appears to underlie the therapeutic efficacy of MR blockade in heart failure (RALES, EPHESUS) and in essential hypertension, providing a rationale for MR blockade in cardiovascular disease not characterized by elevated aldosterone levels. Its wider (patho)physiologic implications, particularly for neurobiology, remain to be explored.     

Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension

The role of aldosterone in the pathogenesis of hypertension and cardiovascular diseases has been clearly shown in congestive heart failure and endocrine hypertension due to primary aldosteronism. In resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP), add-on therapy with mineralocorticoid receptor (MR) antagonists is frequently effective, which we designate as "MR-associated hypertension". The MR-associated hypertension is classified into two subtypes, that with elevated plasma aldosterone levels and that with normal plasma aldosterone levels. The former subtype includes primary aldosteronism (PA), aldosterone-associated hypertension which exhibited elevated aldosterone-to-renin ratio and plasma aldosterone levels, but no PA, aldosterone breakthrough phenomenon elicited when angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) is continued to be given, and obstructive sleep apnea. In contrast, the latter subtype includes obesity, diabetes mellitus, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS). The pathogenesis of MR-associated hypertension with normal plasma aldosterone levels is considered to be mediated by MR activation by pathways other than high aldosterone levels, such as increased MR levels, increased MR sensitivity, and MR overstimulation by other factors such as Rac1. For resistant hypertension with high plasma aldosterone levels, MR antagonist should be given as a first-line therapy, whereas for resistant hypertension with normal aldosterone levels, ARB or ACE-I should be given as a first-line therapy and MR antagonist would be given as an add-on agent.     

Aldosterone-synthase overexpression in heart: a tool to explore aldosterone's effects

Clinical observations indicate that elevated aldosterone impairs cardiovascular function. The mechanisms, however, are not totally understood although total and cardiovascular mortality are decreased by aldosterone antagonists. Experimentally, increased plasma aldosterone induces pericoronary inflammation and cardiac fibrosis. Our laboratory has discovered that aldosterone is synthesized in the rat heart, and has demonstrated that this cardiac aldosterone is involved in post-infarction cardiac remodeling. In man, activated cardiac aldosterone production has been described in patients with heart failure. In transgenic mice that overexpress aldosterone-synthase in the heart, we observe a normal cardiac function but a major coronary dysfunction, more pronounced in males. These observations converge to a potential physiological and pathological relevance of this system. Beneficial effects of anti-aldosterone treatment in heart failure may thus be secondary in part to blockade of cardiac aldosterone action.     

Neues zu Aldosteron und dem Mineralokortikoidrezeptor

The role of mineralocorticoid receptors (MR) in the pathogenesis of cardiovascular and renal diseases is increasingly appreciated. Primary aldosteronism is observed in 8–13% of hypertensive patients, the prevalence being higher in patients with more resistant hypertension. MR participates in the pathogenesis of heart failure, sleep apnea, metabolic syndrome, and nephrotic syndrome. Furthermore, MR mediate aldosterone-induced endothelial dysfunction and adipogenesis. Direct effects of aldosterone on glomerular cells have been demonstrated in animal and in-vitro studies. Reactive oxygen species are important mediators of aldosterone-induced damage to target organs. MRs binds aldosterone and cortisol with similar affinity. Protection from cortisol through 11β-hydroxydehydrogenase 2-mediated inactivation varies among different tissues. Elevated cortisol levels are associated with increased cardiovascular mortality. MR blockade is an attractive treatment; however, life-threatening hyperkalemia may occur. Inhibition of aldosterone synthase may become an attractive alternative for selected patients.     

Aldosterone, mineralocorticoid receptor, and heart failure

Several large clinical studies have demonstrated the important benefit of mineralocorticoid receptor (MR) antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. Aldosterone adjusts the hydro-mineral balance in the body, and thus participates decisively to the control of blood pressure. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical and experimental studies indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels. These deleterious effects include cardiac and renal fibrosis, inflammation and vascular remodeling. It is important to underscore that these effects are due to elevated MR activation that is inadequate for the body salt requirements.Aldosterone is generally considered as the main ligand of MR. However, this is a matter of debate especially in heart. Complexity arises from the glucocorticoids with circulating concentrations much higher than those of aldosterone, and the fact that the MR has a high affinity for 11β-hydroxyglucocorticoids. Nevertheless, the beneficial effects of MR inhibition in patients with heart failure emphasize the importance of this receptor in cardiovascular tissue. Diverse experimental models and strains of transgenic mice have allowed to dissect the effects of aldosterone and the MR in the heart. Taken together experimental and clinical data clearly highlight the deleterious cardiovascular effects of MR stimulation.     

Mineralocorticoid receptor antagonists and hypertension: Is there a rationale?

Accumulating evidence indicates that aldosterone is involved in cardiovascular disease by inducing inflammation in the presence of moderate amounts of salt in the diet. Spironolactone and eplerenone are the mineralocorticoid receptor (MR) antagonists currently available for the treatment of hypertension. They have similar safety and antihypertensive efficacy. The advantage of eplerenone is the lower incidence of antiandrogenic and progestational side effects. The rationale for using MR blockade in the treatment of hypertension is threefold: the evidence of antihypertensive efficacy, the phenomenon of "aldosterone escape" occurring with angiotensin-converting enzyme inhibitor and angiotensin-receptor blockade therapy, and the compelling evidence that MR antagonism reduces target-organ damage in hypertensive patients and improves survival in patients with cardiovascular disease. Thus, blockade of the MR may be very useful in many patients with hypertension, particularly those at risk for or having evidence of target-organ damage.     

Mineralocorticoid Receptor Antagonists and the Metabolic Syndrome

Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.     

Aldosterone, mineralocorticoid receptors and vascular inflammation

For the past 50 years, the physiological action of aldosterone was considered to be on epithelial tissues to maintain fluid and electrolyte homeostasis. Recently, a nonepithelial, pathophysiologic, proinflammatory role for aldosterone has been inferred from studies on mineralocorticoid/salt administration, with or without mineralocorticoid receptor (MR) blockade, in experimental animals, and from clinical studies such as RALES and EPHESUS. More recently still, it has become clear that the pathophysiologic trigger for the vascular inflammatory response observed is not necessarily aldosterone per se, but inappropriate activation of vascular wall MR. MR can be inappropriately activated by aldosterone in the context of an inappropriate salt status, or by glucocorticoids in the context of tissue damage. The studies supporting this latter conclusion, and the novel mechanisms proposed to support this concept, are details in the text to follow.     

Aldosterone as a cardiovascular risk hormone

The pathophysiological role of aldosterone in the development of cardiovascular disease has long been considered to be due its potent volume expansion/hypertensive effect mainly via mineralocorticoid receptor (MR) expressed in renal tubular epithelial cells. However, recent accumulating lines of evidence from clinical and experimental studies have suggested that direct cardiovascular effect of aldosterone contributes to the development of cardiovascular injury via MRs in non-epithelial tissue. A series of recent clinical studies have revealed that patients with primary aldosteronism have higher incidence of cardiovascular and renal complications than those with essential hypertension, and that aldosterone antagonism has cardiovascular protective effect in patients with heart failure independent from blood pressure. Numerous experimental studies have shown that both inflammation and oxidative stress play an initial and key role in the development of aldosterone-induced cardiovascular injury via non-epithelial MR activation. In this review, we discuss recent research progress in aldosterone and MR effects, with special emphasis on the pathophysiological role of aldosterone in cardiovascular diseases and the possible molecular mechanism(s) of cardiovascular injury by non-epithelial MR activation.     

Mineralocorticoid and angiotensin receptor antagonism during hyperaldosteronemia

Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na+-K+ pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na+-K+ pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na+-K+ pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na+-K+ pump current (I(p)), arising from the 3:2 Na+:K+ exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I(p); treatment with losartan reversed aldosterone-induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I(p) at near physiological levels of intracellular Na+ concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.     

Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride

Amiloride was originally described in 1967 as a potassium-sparing diuretic, the mechanism of action of which is to block the epithelial sodium channel (ENaC) within the distal tubule of the kidney. In addition, higher doses of amiloride were found to be capable of inhibiting the Na(+)/H(+) exchangers (NHE) and the Na(+)/Ca(2+) exchangers. In time, several amiloride analogs have been synthesized to have a marked increase in their specificity to inhibit the ENaC, the NHE or the Na(+)/Ca(2+) exchangers. Although the NHE inhibitors have received the most recent attention, large-scale clinical trials using NHE inhibitors in ischemic cardiac states have shown them to be either ineffective or associated with an unacceptable risk profile. Aldosterone excess in animal models is known to cause cardiovascular injury, and blockade of mineralocorticoid receptors in human beings with heart disease improves outcomes. However, the exact mechanisms of aldosterone injury in animal models of hypertensive disease and protection with mineralocorticoid receptor antagonists in human trials of heart failure remain unknown. These effects are unexplained by changes in BP, potassium, or sodium balance. An additional possibility is that aldosterone action and mineralocorticoid receptor blockade is conferred by alterations in ENaC activity. Emerging experimental evidence suggests the possibility that systemic or central ENaC inhibition or both may be an alternative to the treatment of hypertension and cardiovascular disease states. Clinical trials to evaluate further the potential beneficial cardiovascular effects of ENaC blockade are needed. This article reviews the case for ENaC inhibition as a potential target for cardiovascular and renal protection in human beings.     

Aldosterone as an endogenous cardiovascular toxin and the options for its therapeutic management

In physiological, as well as pathological situations, aldosterone significantly influences volume, pressure and electrolyte balance. Primary hyperaldosteronism is caused by autonomous over-production, most frequently due to adrenal adenoma. Patients with primary hyperaldosteronism (Conn's syndrome) have more pronounced left ventricular hypertrophy and higher frequency of cardiovascular events than patients with essential hypertension (EH) with comparable blood pressure values. Consequently, there is an increased interest in the role ofaldosterone tissue function in cardiovascular disease. The aim of the present paper is to emphasise the pleiotropic actions of aldosterone on cardiovascular system and the options for their therapeutic management. Apart from the effects of circulating aldosterone on BP and its renal actions on water and electrolyte excretion, extra-renal effects are also been explored; paracrine affects through tissue mineralocorticoid receptors (MR) may impact on endothelial dysfunction, vascular elasticity, inflammatory changes in the myocardium, vessels and kidneys. Initial oxidative stress due to increased aldosterone concentrations may initiate subclinical endothelial changes and subsequent myocardial fibrosis. The effects on all three layers of vascular wall, together with increased blood coagulation and vascular thrombogenicity increases likelihood of microthrombosis and tissue microinfarctions. Slight increase in aldosterone concentrations in cardiac tissue adversely affects myofibrils as well as coronary artery function. Similar to peripheral vessels, it increases collagen content and changes vascular rigidity and the velocity of pulse wave and facilitates development of perivascular fibrosis. Higher salt intake may potentiate these pathophysiological effects of aldosterone, while higher intake of potassium may restrict them. Aldosterone vasculopathy together with perivascular fibrosis occurring at aldosterone concentrations seen with heart failure contributes to manifestation of heart failure. Consequently, aldosterone may rightly be called "cardiovascular toxin". The adverse effects of aldosterone in patients on long-term ACEI therapy are further facilitated by the aldosterone's ability to evade inhibitory effects of ACEI and parallel activation of renin-angiotensin system. To manage these situations, receptors of mineralcorticoids or direct renin inhibitor aliskiren are used. The positive effect of MR blockade is based on an increased release of nitric oxide (NO) with further improvement in endothelial functions. Detailed review of pleotropic effects of aldosterone helps to clarify a number of pathophysiological situations in essential hypertension, supports the view ofaldosterone as a potential cardiovascular toxin and indicates the use of mineralocorticoid receptor blockers in resistant hypertension and patients with cardiovascular or renal organ damage.     

Induction of cardiac fibrosis by aldosterone

An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11beta-hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV reduces total mortality by 30%.     

Aldosterone Synthase Inhibition in Hypertension

Hypertension is an established risk factor for stroke, premature coronary artery disease and heart failure. Control of elevated blood pressure has been shown to result in significant reduction of cardiovascular risk. Aldosterone, the final product of the renin–angiotensin–aldosterone system (RAAS), not only causes salt and water reabsorbtion in the kidneys through its effect on the mineralocorticoid hormone receptor (MR), but also an MR-independent effect, not regulated by conventional MR blockade. Although many pharmacological agents target different levels of the RAAS cascade, these generally result in elevated renin concentration and plasma renin activity. This upstream feedback response subsequently results in elevated levels of angiotensin II, a potent vasoconstrictor and stimulus to aldosterone release. This aldosterone breakthrough counteracts the long-term blood pressure–lowering effect of these agents. Therefore the development of a new class of pharmacologic agents that directly inhibit the production of aldosterone may prove clinically useful in reducing aldosterone and thereby controlling elevated blood pressure.     

Aldosterone and cardiovascular risk

Through its classic effects on sodium and potassium homeostasis, aldosterone, when produced in excess, is associated with the development of hypertension and hence with higher cardiovascular and renal risk. In recent years, experimental and epidemiologic data have suggested that aldosterone also may be linked to high cardiovascular risk independently of its effects on blood pressure. Thus, aldosterone has been associated with obesity and metabolic syndrome in selected populations, and these associations may further contribute to the higher cardiovascular risk of subjects with elevated aldosterone levels. Moreover, aldosterone has been reported to promote inflammation, oxidative stress, and fibrosis in a number of tissues. Clinical evidence indicates that patients with primary hyperaldosteronism have a higher risk of developing cardiovascular and renal complications than patients with essential hypertension who have the same level of blood pressure. Aldosterone receptor blockade has been shown to lower cardiovascular mortality after myocardial infarction and in patients with congestive heart failure. Some studies have also demonstrated that aldosterone blockade could have a favorable impact on the progression of renal disease. However, prospective interventional trials are needed to further evaluate the impact of blockade of aldosterone on cardiovascular risk.     

Long‐term BP control and vascular health in patients with hyperaldosteronism treated with low‐dose,amiloride‐based therapy

Whether aldosterone itself contributes directly to macro‐ or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long‐term single‐practice experience in 5 patients with chronic hyperaldosteronism (HA, including 3 with glucocorticoid remediable aldosteronism, GRA) treated with low‐dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5‐10 (mean 7) mg daily for 14‐28 (mean 20) years. Except for 1 GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normal or near‐normal within 1‐4 weeks after starting amiloride and office BP’s were well controlled for 20 years thereafter. Vascular studies and 24‐hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, and reflection magnitude) were assessed after a mean of 18 years as were regional pulse wave velocities, pulse stiffening ratio, ankle‐brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio. All indicators were completely normal in all patients after 18 years of amiloride, and none had a cardiovascular event during the 20‐year mean follow‐up. We conclude that long‐term ENaC blockade can normalize BP and protect macro‐ and microvascular function in patients with HA. This suggests that (a) any vasculopathic effects of aldosterone are mediated via ENaC, not MR activation itself, and are fully preventable or reversible with ENaC blockade or (b) aldosterone may not play a major BP‐independent role in human macro‐ and microcirculatory diseases. These and other widely divergent results in the literature underscore the need for additional studies regarding aldosterone, ENaC, and vascular disease.