Mechanisms of mineralocorticoid salt-induced hypertension and cardiac fibrosis

For 50 years aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues such as the heart and vascular smooth muscle. Recently pathophysiologic effects of nonepithelial MR activation by aldosterone have been demonstrated, in the context of inappropriate mineralocorticoid for salt status, including coronary vascular inflammation and cardiac fibrosis. Consistent with experimental studies, clinical trials (RALES, EPHESUS), have demonstrated a reduced mortality and morbidity when MR antagonists are included in the treatment of moderate-severe heart failure. The pathogenesis of MR-mediated cardiovascular disease is a complex, multifactorial process that involves loss of vascular reactivity, hypertension, inflammation of the vasculature and end organs (heart and kidney), oxidative stress and tissue fibrosis (cardiac and renal). This review will discuss the mechanisms by which MR, located in the various cell types that comprise the heart, plays a central role in the development of cardiomyocyte failure, tissue inflammation, remodelling and hypertension.     

The Kidneys and Aldosterone/Mineralocorticoid Receptor System in Salt-Sensitive Hypertension

Strong evidence supports the ability of the aldosterone/mineralocorticoid receptor (MR) system to dominate long-term blood pressure control. It is also increasingly recognized as an important mediator of cardiovascular and renal diseases, particularly in the presence of excessive salt intake. In a subgroup of individuals with metabolic syndrome, adipocyte-derived aldosterone-releasing factors cause inappropriate secretion of aldosterone in the adrenal glands during salt loading, resulting in the development of salt-induced hypertension and cardiac and renal damage. On the other hand, emerging data reveal that aldosterone is not a sole regulator of MR activity. We have identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of salt-sensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade.     

Discussion for Drs. Winquist and Napier

The classical effects of aldosterone are mediated via epithelial mineralocorticoid receptors (MR), protected against cortisol/corticosterone occupancy and activation by the enzyme 11β hydroxysteroid dehydrogenase. The pathophysiological effects of aldosterone on non-epithelial tissues, in contrast, are mediated via unprotected MR in which occupancy by cortisol/corticosterone antagonises the effect of aldosterone. Aldosterone raises blood pressure by occupying MR in the circumventricular region of the brain, an effect antagonised by concomitant intracerebroventricular (ICV) infusion of similar doses of corticosterone. Peripheral infusion of aldosterone to salt loaded rats causes hypertension, cardiac hypertrophy and cardiac fibrosis; concomitant ICV infusion of the MR antagonist RU28318 abolishes the aldosterone-induced hypertension, but does not affect cardiac hypertrophy or fibrosis. These peripheral effects of aldosterone are presumably via cardiac MR; high glucose/PKC modulated, aldosterone-specific effects on protein synthesis have recently been demonstrated as direct MR-mediated actions on cultured neonatal rat cardiomyocytes. The pathophysiologic effects of aldosterone via non-epithelial MR have a time course of days/weeks rather than hours, reflect occupancy of only a small percentage of such receptors, and require salt loading. How the effects of salt loading are transduced in such circumstances remains to be explored.     

Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status.

In recent years, it has been clarified that aldosterone can directly damage various organs, such as the heart, blood vessel, and kidneys, via non-epithelial mineralocorticoid receptors, independent of changes in blood pressure. Anti-aldosterone drugs have been clinically reported to be useful for their organ-protecting effects. The fact that these effects have been considered important for almost 10 years seems to indicate that aldosterone-induced organ damage can develop as a consequence of plasma aldosterone levels being in disproportion to salt status. In a previous study, cardiac fibrosis could not be induced in an experimental model of hyperaldosteronism with a low-salt diet. It is, therefore, extremely important to understand the relationship between plasma aldosterone level and inappropriate salt balance when considering diseases or states for which an anti-aldosterone drug is called for. In this paper we review the fundamental and clinical studies reported to date, mainly to investigate the pathology of organ damage induced by aldosterone and excess salt. Aldosterone-induced direct organ damage mediated through vasculitis essentially requires salt, which is inappropriate for plasma aldosterone level, and studies performed from this standpoint may provide a clue to the clarification of the involvement of salt in the actions of aldosterone via non-epithelial mineralocorticoid receptors. In humans, it is also strongly suggested that organ damage may occur, even at a plasma aldosterone level within a normal range, if salt intake is imbalanced to the aldosterone level. This means that the new aldosterone blocker eplerenone may also have significance as a drug inhibiting inflammation, possibly serving as a trigger of organ damage.     

Aldosterone as a cardiovascular risk factor.

Aldosterone exerts cardiovascular effects by influencing epithelial fluid and electrolyte excretion, and thus blood volume and pressure. Mineralocorticoid receptors (MR) are found in epithelial and non-epithelial tissues (vessel walls, heart, brain), with high affinity for aldosterone and physiological glucocorticoids cortisol and corticosterone. MR blockade by spironolactone or eplerenone favorably affects cardiovascular outcomes. In some situations (primary aldosteronism, experimental mineralocorticoid administration) activation of cardiovascular MR reflects aldosterone levels inappropriate for salt status. In others (heart failure, essential hypertension) aldosterone and Na(+) status are often normal pretreatment; cardiovascular MR may thus be activated by normal glucocorticoid levels after tissue damage and reactive oxygen species generation. Therefore, although unilateral adrenalectomy is preferred therapy for unilateral aldosterone-producing adenoma or hyperplasia, MR blockade may be useful in cardiovascular diseases where aldosterone levels are normal.     

Interactions of high salt intake and the response of the cardiovascular system to aldosterone

High salt intake contributes to the risk of hypertension, and this effect is in part mediated by the physiologic action of aldosterone on renal mineralocorticoid receptors. However, the actions of aldosterone are not restricted to the kidneys, because aldosterone can bind to mineralocorticoid receptors in the heart, vasculature, and brain to produce structural and functional changes that lead to target organ damage. Experimental and clinical studies show that, in the setting of high salt intake, blocking aldosterone at the mineralocorticoid receptor reduces progression to target organ damage and preserves vascular function. In many cases, these benefits are independent of changes in blood pressure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have short-term effects on reducing aldosterone levels, but frequently aldosterone levels return to pretreatment levels during long-term therapy. Aldosterone blockade may be more completely achieved with mineralocorticoid receptor antagonists. Spironolactone has been shown to have substantial and significant benefits in experimental and clinical studies of cardiac dysfunction. Eplerenone is a selective aldosterone blocker with a greater binding affinity for mineralocorticoid receptors than for androgen and progesterone receptors. Eplerenone has similarly demonstrated significant benefits in experimental animals and in patients with left ventricular dysfunction after myocardial infarction. Thus, aldosterone blockade with mineralocorticoid receptor antagonists offers target organ protection and may blunt some of the adverse effects of chronic high salt intake.     

Hyperaldosteronismus und verst?rkte Aktivit?t des Mineralokortikoidrezeptors

Aldosterone is an adrenal hormone with pleitropic activity. It stimulates the mineralocorticoid receptor (MR), which modulates numerous physiological and pathophysiological processes. Increased receptor activity together with inappropriate salt intake leads to arterial hypertension as well as inflammatory and fibrotic tissue remodeling. In addition, numerous other pathways in tissue remodeling, including renal protein excretion, are affected. Common causes of increased MR activity are unilateral adrenal adenoma and bilateral hyperplasia producing an excess of aldosterone. Therapy for these conditions is unilateral adrenalectomy, if appropriate, or pharmacological MR blockade. Current studies to improve management of this condition focus on the development of new, more selective modulators of MR activity with fewer side effects and clinical studies to broaden the usage of MR blockers.     

Eplerenone, but not steroid withdrawal, reverses cardiac fibrosis in deoxycorticosterone/salt-treated rats

Aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues, such as the heart and vascular smooth muscle. Recently, pathophysiological effects of nonepithelial MR activation by aldosterone have been demonstrated in the context of inappropriate mineralocorticoid levels for salt status, including coronary vascular inflammation and cardiac fibrosis. These effects are mostly prevented by the concomitant administration of MR antagonists, but to date, no equivalent studies have determined whether MR blockade can reverse established inflammation and fibrosis. Uninephrectomized rats maintained on 0.9% NaCl solution to drink were treated as follows: group 1 served as controls; group 2 received deoxycorticosterone (DOC; 20 mg/wk) for 4 wk until death, and group 3 received DOC for 8 wk. Group 4 received DOC for 4 wk and no steroid from wk 5-8; group 5 received DOC for 8 wk and eplerenone in their chow during wk 5-8. DOC progressively raised cardiac collagen accumulation at 4 and 8 wk. Rats given DOC for 4 wk and killed at 8 wk showed levels of fibrosis identical to those in animals killed at 4 wk, i.e. persistently elevated above control values. Rats given DOC for 8 wk and eplerenone for the second half of the period showed cardiac collagen levels indistinguishable from control values. Values for inflammatory marker and NAD(P)H oxidase subunit expression in coronary vessels showed a similar pattern of response, with minor variation. Thus, MR antagonists do not only prevent cardiac fibrosis, but also reverse cardiac fibrosis once it is established. In addition, the continuing vascular inflammatory response and fibrosis after DOC withdrawal (group 4) support a role for activation of vascular MR by endogenous glucocorticoids in the context of tissue damage and generation of reactive oxygen species.     

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.     

Aldosterone target organ protection by eplerenone

The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant effect of this hormone. However, there is convincing evidence for additional extrarenal actions of aldosterone that are mediated via activation of mineralocorticoid receptors (MRs) in the heart, vasculature and brain. It is now postulated that many of the detrimental effects of aldosterone are mediated through MR activation in these nonclassical target organs. The selective aldosterone blocker, eplerenone (Inspra), is under development for human therapeutic use for treatment of hypertension and heart failure post-myocardial infarction (MI). Clinical and preclinical studies have linked elevated aldosterone to hypertension, left ventricular and vascular remodeling, cardiac, renal, and cerebral vascular inflammation and injury, and increased risk of mortality in heart failure patients. Multiple studies in experimental models of hypertension and heart failure demonstrate that selective blockade of aldosterone by eplerenone effectively preserves cardiac function, attenuates maladaptive left ventricular remodeling and tissue and vascular injury in part by reducing vascular inflammation in aldosterone target organs.     

Low renin hypertensive states: perspectives, unsolved problems, future research.

Some causes of low renin hypertension are familial with known genetic bases. One of them, primary aldosteronism, is specifically treatable by mineralocorticoid receptor blockers or by surgery, and has at least two different familial varieties. These have provided insights into its natural history, with long normotensive and normokalemic phases, and variable expression within the same family. Primary aldosteronism was considered rare, but recent work beginning in 1992 suggests that it might be the most common curable cause of hypertension, worth screening for in every hypertensive. Evidence is now compelling that inappropriate aldosterone for salt status can cause not only hypertension, but vascular inflammation and end-organ damage, preventable by mineralocorticoid receptor blockade.     

Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.     

Mineralocorticoid receptors in vascular function and disease

The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone (Aldo) on renal sodium handling. Over the past decade, it has become clear that MR is expressed in the cardiovascular system and interest has grown in understanding the direct role of the MR in regulating vascular function and contributing to cardiovascular disease. This interest stems from multiple clinical studies in which drugs that decrease MR activation also reduce the incidence of heart attacks, strokes, and mortality out of proportion to modest changes in systemic blood pressure. The presence of functional mineralocorticoid receptors in vascular smooth muscle and endothelial cells is now well established and, while still controversial, data supports the vasculature as an Aldo-responsive tissue. This review summarizes recent advances in our understanding of the role of vascular MR in regulating normal vascular function and in promoting vascular disease. In vitro data, in vivo animal studies, and human data are reviewed suggesting a role for MR-activation in promoting vascular oxidative stress, inhibiting vascular relaxation, and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, vascular MR activation may promote vascular aging and atherosclerosis thereby contributing to the pathophysiology of heart attack, stroke, and possibly even hypertension. Further exploration of the molecular mechanisms for the detrimental vascular effects of MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders.     

Aldosterone and vascular damage

Although the aldosterone escape mechanism is well known, aldosterone has often been neglected in the pathophysiologic consequences of the activated renin-angiotensinaldosterone system in arterial hypertension and chronic heart failure. There is now evidence for vascular synthesis of aldosterone aside from its secretion by the adrenal cortex. Moreover, aldosterone is involved in vascular smooth muscle cell hypertrophy and hyperplasia, as well as in vascular matrix impairment and endothelial dysfunction. The mechanisms of action of aldosterone may be either delayed (genomic) or rapid (nongenomic). Deleterious effects of aldosterone leading to vascular target-organ damage include (besides salt and water retention) decreased arterial and venous compliance, increased peripheral vascular resistance, and impaired autonomic vascular control due to baroreflex dysfunction.     

Aldosterone and the Risk of Hypertension

Aldosterone, the key hormone in the mineralocorticoid pathway, plays a fundamental role in salt and water homeostasis, blood pressure regulation, and cardiovascular remodeling. Both genomic and nongenomic mechanisms influence aldosterone-induced renal sodium reabsorption. Furthermore, the mineralocorticoid receptors in nonepithelial tissues, including the heart and vascular smooth muscle cells, have recently been discovered. Thus, aldosterone likely has pleiotropic effects that contribute to the modulation of blood pressure. Among patients with hypertension in general, and among those with more severe or resistant hypertension in particular, a higher-than-expected prevalence of primary hyperaldosteronism is noted. Among individuals with resistant hypertension, aldosterone antagonists have also been shown to be effective in lowering blood pressure. Most significantly, recent community-based studies among non-hypertensive individuals in the general population have demonstrated that both higher serum aldosterone concentrations and a higher aldosterone to renin ratio portend a greater risk of developing hypertension. The combination of the aforementioned observations underscores the importance of the mineralocorticoid pathway in the pathogenesis of hypertension.