toward a broader understanding of aldosterone in congestive heart failure

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DOI: 10.3317/jraas.2003.024

2003 4: 155Journal of Renin-Angiotensin-Aldosterone SystemKenneth J Warrington

Karl T Weber, Yao Sun, Linus A Wodi, Ahmad Munir, Eiman Jahangir, Robert A Ahokas, Ivan C Gerling, Arnold E Postlethwaite andToward a broader understanding of aldosterone in congestive heart failure

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Journal ofthe Renin-Angiotensin-AldosteroneSystem(Including otherpeptidergic systems)

September 2003Volume 4Number 3

155

Toward a broader understanding of aldosterone in congestive heart failureKarl T Weber,* Yao Sun,* Linus A Wodi,* Ahmad Munir,* Eiman Jahangir,*Robert A Ahokas,† Ivan C Gerling,≠ Arnold E Postlethwaite,§ Kenneth J Warrington §

Keywords: aldosterone, magnesium,peripheral bloodmononuclearcells,oxi/nitrosativestress

Divisions of*CardiovascularDiseases,≠Endocrinology,§Connective TissueDiseases,Department ofMedicine, andDepartment of†Obstetrics &Gynecology,University of TennesseeHealth Science CenterMemphis, TNUSA

Correspondence to:Dr Karl T WeberDivision ofCardiovascularDiseases,University of TennesseeHealth Science Center,Rm. 353 DobbsResearch Institute,951 Court Avenue,Memphis, TN 38163,USATel: +1 901 448 5750Fax: +1 901 448 8084E-mail: [email protected]

Accepted for publication8th July 2003

JRAAS 2003;4:155–63

AbstractDiscovered some 50 years ago, aldosterone (ALDO)has come to be recognised as a mineralocorticoidhormone with well-known endocrine properties inepithelial cells that contribute to the pathophysiologyof congestive heart failure. This includes Na+

resorption at the expense of K+ excretion in classictarget tissues: kidneys, colon, sweat and salivaryglands. Though less well known, Mg2+ excretion islikewise enhanced by ALDO, while adrenal ALDOsecretion is regulated by extracellular Mg2+ ([Mg2+]o).An emerging body of information has and continuesto identify other endocrine actions of ALDO receptor-ligand binding. They include: promoting anefflux of cytosolic free Mg2+, or [Mg2+]i, in exchangefor Na+ in such non-epithelial cells as peripheral bloodmononuclear cells; its influence on endothelial cellfunction; and its central actions that involve regulation of cerebrospinal fluid composition produced by epithelial cells of the choroid plexus,activity of the hypothalamic paraventricular nucleusinvolved in Na+ appetite, Na+ and H2O excretion andsympathetic nerve activity, and the regulation of TNF-α production from central and/or peripheralsources. Extra-adrenal steroidogenesis and auto/paracrine properties of ALDO generated de novoin the cardiovasculature are now under investigationand preliminary findings suggest they contribute totissue repair. The past decade has witnessed a revivalof interest in this steroid molecule. In years to come,an even broader understanding of ALDO’s contribution to the pathophysiology of congestiveheart failure will undoubtedly emerge.

IntroductionAldosterone (ALDO) was discovered some 50years ago.1,2 Termed electrocortin, identification ofits 18-aldehyde steroid structure and adrenalorigin led to its being renamed aldosterone(ALDO). ALDO’s ability to alter Na+ uptake inexchange for K+ prompted Selye to refer to it as amineralocorticoid.3 During a decade of discoverythat followed its identification, sites of ALDO’saction and receptor-ligand binding were found toreside within epithelial cells of the kidney, colon,sweat and salivary glands.4,5 The importance ofthis circulating hormone in promoting salt andwater retention at each of these target tissues wasdemonstrated in such oedema-forming states ascongestive heart failure (CHF). Also confirmatoryof its importance in CHF was the efficacy of

spironolactone, an ALDO receptor antagonistintroduced into clinical practice 45 years ago, incounteracting Na+ retention and alleviatingoedema.4-8

A recent resurgence of interest in this steroidmolecule in CHF has been driven by several obser-vations.9 In brief, this included: a recognition ofALDO’s broader range of actions that extendedbeyond classic target tissues and which were asso-ciated with an adverse structural remodelling ofthe cardiovasculature that contributes to patho-physiologic expressions and progressive nature ofCHF;10 the inability of angiotensin-convertingenzyme (ACE) inhibition to provide for sustainedsuppression of plasma ALDO in patients withCHF,11,12 which indicated that the regulation of itssecretion by zona glomerulosa cells of the adrenalcortex is more complex than that governed byangiotensin II (Ang II) alone;and finally, the resultsof a controlled clinical trial (RandomisedALdactone Evaluation Study [RALES]), conductedin 19 countries on five continents in over 1,600patients with CHF, wherein spironolactone (vis-à-vis placebo), in combination with an ACE inhibitor(ACE-I) and loop diuretic, reduced the risk of all-cause and cardiac-related mortality and cardiovas-cular morbidity by 30%.13

Herein, less well recognised properties ofALDO, mediated by receptor-ligand binding, arebriefly reviewed. Each has the potential to con-tribute to the pathophysiology of CHF. Theyinclude its influence on: Mg2+ balance and the roleof extracellular Mg2+ [Mg2+]o in regulating adrenalALDO secretion; vascular remodelling andimmune cell activation; endothelial cell function;and the central nervous system. Finally, extra-adrenal steroidogenesis of ALDO by the cardiovas-culature is briefly considered. The interestedreader is referred elsewhere14 for a discussion ofnon-genomic, non-receptor-mediated actions ofALDO.

Aldosterone and Mg2+ balance The distribution of Mg2+ within body tissues is asfollows: 53% in bone, 27% in skeletal muscle and19% in other soft tissues, such as the heart; lessthan 1% of total body Mg2+ is present in blood; andcytosolic free Mg2+ [Mg2+]i, represents but 0.5–5%of total cellular Mg2+, with the remaining 80%bound to ATP and other phosphometabolitessequestered within such organelles as mitochondria

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and endoplasmic reticulum.15 [Mg2+]i homeostasisis maintained by exchange with these intracellularstores, while [Mg2+]o is held within narrow limitsby Mg2+ efflux from tissue stores.

Epithelial cellsIn 1955, Mader and Iseri16 reported that theirpatient with adrenal adenoma had experiencedspontaneous episodes of hypomagnesaemia,together with enhanced Mg2+ excretion in urineand stool. Others17-24 would also note the presenceof hypomagnesaemia in patients with primaryaldosteronism (PAL), suggesting Mg2+ deficiencyaccompanies long-standing, ALDO-induced Mg2+

excretion.These clinical findings implicated ALDOin regulating both K+ and Mg2+ excretion in classictarget tissues. Horton and Biglieri25 addressedurinary K+ and Mg2+ excretion in five patients withPAL, each of whom had low normal or reducedserum Mg2+ levels, and reported their findings in1962. The influence of surgical resection ofadrenal adenoma on urinary K+ and Mg2+ excretionwas assessed in two patients (Figure 1). In both,there was an immediate and marked fall in excre-tion of these mono- and divalent cations aftersurgery, together with a gradual normalisation ofplasma Mg2+. A lower basal excretion of Mg2+, com-parable to values seen for normal controls on thesame Mg2+ diet, was seen post-operatively. In athird patient, spironolactone was shown to reduceboth urinary K+ and Mg2+ excretion, both of whichreturned to previous increased basal levels follow-ing spironolactone discontinuation (Figure 2).Thus, the importance of ALDO in promoting

urinary Mg2+ excretion was evident. Conn, whohad coined the term PAL in 1954 to connoteautonomous adrenal ALDO production indepen-dent of plasma renin activity, reviewed his person-al series of 18 cases of PAL in 1963. Together withanother 127 that had been reported in the literature,

156

HEART FAILURE AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

Figure 1 Urinary K+ and Mg2+ excretion in two patients with primary aldosteronism, before and after surgical removal ofadrenal adenoma. Serum K+ and Mg2+ levels are shown for one of these individuals. See text. Reproduced with permissionfrom reference25

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he concluded that hypomagnesaemia, togetherwith hypokalaemia, hypernatraemia, hypochlo-raemia and metabolic alkalosis, were the cardinalmetabolic abnormalities of PAL.26

The importance of the adrenal cortex in regu-lating Mg2+ and K+ excretion was further under-scored in the setting of adrenal insufficiency oradrenalectomy.27-31 ALDO treatment of dogs or ratswith surgically-induced bilateral adrenalectomywas shown to increase faecal K+ and Mg2+ excre-tion and to normalise their plasma concentra-tions.32,33 Horton and Biglieri25 treated an adrena-lectomised patient with d-ALDO for eight days(Figure 3); on day five of this regimen, spironolac-tone co-treatment was initiated. Exogenous ALDOpromoted a prompt elevation in urinary K+ andMg+ excretion that was abrogated by the ALDO-receptor antagonist. Thus, the body of evidence iscompelling that ALDO promotes both K+ and Mg2+

excretion at classic target tissue sites.Mg2+ excretion is likely to be increased in

patients with CHF, in whom elevated plasma ALDOlevels are expected. In patients with CHF treatedwith a loop diuretic, there exists an independentstimulus to urinary Mg2+ excretion and the poten-tial for exaggerated Mg2+ loss.34, 35 Detection of bio-logically active, cytosolic free [Mg2+]i (vis-à-vis itsconcentration in serum, which does not reflectintracellular Mg2+) hinders the detection andassessment of this important clinical problem.Intracellular Mg2+ deficiency may contribute tomorbid and mortal events, such as sudden cardiacdeath, that occurs in 50% of patients with CHF.36

The 30% reduction in risk of sudden cardiac deathobserved in the RALES trial may, in part, be relatedto spironolactone’s ability to restore and preserveMg2+ homeostasis.

Non-epithelial cellsALDO regulates Mg2+ exchange by non-epithelialcells, such as peripheral blood mononuclear cells(PBMC). ALDO binds to a single class of cytosolicreceptors in these cells.37 In patients with eitherPAL or renin-dependent, secondary aldosteronism(SAL),ALDO binding sites are reduced by 50%; fol-lowing surgical removal of adenomatous adrenaltissue, receptor binding in PBMC is normalised.38,39

ALDO promotes the efflux of Mg2+ from culturedhuman lymphocytes in exchange for Na+ viareceptor-ligand binding. This response, measuredby a fluorescent probe (Mag-fura-2), is dependenton extracellular Na+ and involves both transcrip-tion and protein synthesis, as demonstrated by itsrespective abrogation by cycloheximide and actin-omycin D.40 Lymphocyte ionised [Mg2+]i is reducedin patients with PAL secondary to either adrenaladenoma or hyperplasia.40 In uninephrectomisedrats treated with ALDO by implanted minipump,we found PBMC [Mg2+]i to be significantlyreduced41 and accompanied by immune cell acti-vation.42,43

Mg2+ and aldosterone secretion Extracellular Mg2+ ([Mg2+]o) participates in the reg-ulation of adrenal ALDO secretion to create apathway of reciprocal regulation in Mg2+ home-ostasis (Figure 4). In healthy, normotensive menand women, an intravenous infusion of MgSO4 ofseveral hours' duration will suppress plasmaALDO levels.44,45 Dietary-induced Mg2+ deficiencywith reduced [Mg2+]o, on the other hand, is accom-panied by an expanded width to the adrenal zonaglomerulosa, together with hyperplasia of therenal juxtaglomerulosa cell, increased adrenalALDO secretion, increased plasma ALDO and areduction in urinary Na+/K+ ratio.46-50 A high Na+


Figure 3 Urinary K+ and Mg2+ excretion in a patientwith bilateral adrenalectomy before and during aldosterone treatment (without and then with oralspironolactone coadministration). See text. Reproducedwith permission from reference25

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ADRENAL ALDO SECRETION

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diet, combined with dietary Mg2+ deficiency, atten-uates, but does not abrogate, heightened ALDOsecretion.48 In cultured zona glomerulosa cells,superfusate [Mg2+]o regulates ALDO production:high [Mg2+]o suppresses,while a [Mg2+]o free mediaaugments, their elaboration of ALDO.51 The SALthat accompanies dietary Mg2+ deficiency is asso-ciated with a time-dependent rise in [Na+]i and[Ca2+]i in heart, skeletal muscle, kidney and bone,which is suggestive of an inhibition of Na,K ATPase, a Mg2+-dependent pump, and increasedNa+/Ca2+ exchange at these sites.52-54

Vascular remodelling and immunecell activationA structural remodelling of the cardiovasculatureby fibrous tissue accompanies aldosteronismderived from either endogenous or exogenoussources.55-63 This fibrogenic phenotype includesintramural arteries of the heart, kidney, pancreas,mesentery and vasa vasorum of aorta and pul-monary artery.Co-treatment with a receptor antag-onist (e.g., spironolactone, eplerenone), in eithernon-depressor or depressor doses, prevents thisremodelling, indicating its independence of eleva-tions in blood pressure (BP).58,61-69 In a substudy tothe RALES trial, survival benefit was associatedwith a reduction in circulating markers of collagensynthesis that presumably reflected an attenuationin ongoing vascular fibrosis.70 In this connection,urinary excretion of hydroxyproline, a marker ofcollagen turnover, is increased in adrenalec-tomised rats treated with ALDO, 1% dietary NaCl,and cortisone.70 Glucocorticoids, on the otherhand, are known to reduce urinary hydroxypro-line excretion and their inhibition of collagen for-mation in bone is associated with osteoporosis.71

Campbell et al.60 and Nicoletti and co-workers61 each found that the perivascular fibrosisof the coronary vasculature that ultimatelyappears in aldosteronism is preceded by a pro-inflammatory vascular phenotype that featuresinvading monocytes/macrophages and lympho-cytes and adhesion molecule expression. Thesefindings, including their independence of BP, weremore recently confirmed by others.63,68,69 An inter-rogation of molecular responses involved in theinvasion of coronary vessels by these inflammato-ry cells were recently addressed in animal modelsof PAL and SAL.62,72 In rats receiving ALDO/salttreatment (ALDOST),where plasma renin and AngII are each suppressed, Sun et al.72 tested thehypothesis that oxidative stress was involved inthe appearance of the pro-inflammatory/fibro-genic cardiac phenotype. At week 3 of ALDOST,there was no evidence of cardiac pathology; atweeks 4 and 5, however, inflammatory cells(monocytes/macrophages and lymphocytes) werefound to have invaded intramural coronary vesselsin both ventricles. Using immunohistochemistry,invading PBMC were found to express the gp91phox

subunit of NADPH oxidase, whose activation is amajor source of superoxide in leukocytes, and 3-nitrotyrosine, a product of peroxynitrite withstable protein tyrosine residues and where perox-

ynitrite is formed by the reaction between super-oxide and nitric oxide (NO). The RelA subunit ofNFκB, a redox-sensitive transcription factor inte-gral to inflammatory responses, was likewise acti-vated in these cells. In situ hybridisation localisedincreased mRNA expression of intercellular adhe-sion molecule (ICAM)-1, monocyte chemoattrac-tant protein (MCP)-1, and a pro-inflammatorycytokine tumour necrosis factor (TNF)-α at vascu-lar sites that involved the normotensive, non-hypertrophied right atrium and ventricle and leftatrium, as well as the hypertensive, hypertrophiedleft ventricle. Co-treatment with either spirono-lactone or an antioxidant (either pyrrolidinedithiocarbamate or N-acetylcysteine) preventedthe appearance of these cells and associated mol-ecular responses, as well as the subsequentperivascular fibrosis. Thus, ALDOST inducesoxi/nitrosative stress within inflammatory cellsinvading the intramural coronary vasculature andit is this pro-inflammatory vascular phenotype thatleads to intramural coronary artery pathology andthe subsequent perivascular fibrosis. Why shouldthis be the case? Did this only occur at vascularsites or was there a prior activation of PMBC?

We recently identified an ALDO-mediatedreduction in [Mg2+]i that appears in PBMC at week1 of ALDOST,43 long before the appearance ofcardiac pathology at week 4. The early activationof these cells is evident in their transcriptome(expressed genes) and proteome (expressed pro-teins).42,43 The interrogation of complex molecularevents that account for immune cell activation andsubsequent homing of these cells to the heart,mayexplain why cardiac pathology does not appearuntil week 4 of ALDOST and calls into questionthe prospect of an autoimmune response, notunlike that which can follow myocardial infarction(MI).73

In rodents treated with a Mg2+-deficient diet, aputative state of exaggerated aldosteronism (seeabove), lymphocyte Mg2+ is reduced to an extentcomparable to the Mg2+ depletion that appears inskeletal muscle and cardiac tissue.74 Weglicki andco-workers have identified an early (week 1)induction of oxi/nitrosative stress and depletionof antioxidant defences in PBMC and endothelialcells.75-78 The lymphocyte activation featured hereincludes their production of proinflammatorycytokines and a neurogenic peptide, substance P,together with the expression of its receptors.79

Cardiac lesions first appear in this model duringweek 3 and can be prevented by a substance Preceptor antagonist.79

The potential for the SAL that accompanieshuman CHF to likewise be accompanied byimmune cell activation remains unexplored.Nonetheless, the prospect exists that the nowrecognised ‘cytokine storm’ of CHF, which featureselevations in such circulating proinflammatorycytokines as TNF-α and IL-6, has an immune cellorigin. Cells of the monocyte-phagocyte systemare a potent source of these cytokines. An alter-native source of cytokine production in heartfailure is the central nervous system.80


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Irrespective of their origin, prolonged elevationsin these proinflammatory cytokines contribute tothe progressive systemic illness that accompaniesCHF and which features tissue wasting to eventu-ate in cardiac cachexia.81

Endothelial cell dysfunctionIn patients with PAL or renal artery stenosis withSAL, forearm vasomotor reactivity to endothelialcell-dependent acetylcholine is diminished com-pared with normotensive controls, while non-endothelial cell-dependent sodium nitroprusside-induced vasodilatation is preserved.82 Four weeksafter surgical removal of adrenal adenoma, theimpairment in endothelial cell-dependent vasodi-lation is restored. In the SAL that accompaniesCHF, Farquharson and Struthers83 found dimin-ished forearm vasomotor reactivity to acetyl-choline to be normalised after one month ofspironolactone treatment. Acetylcholine-induced,NO-dependent vasorelaxation of aortic rings isreduced in rats following MI.84 This vasomotordysfunction, together with increased superoxideformation by aortic tissue, is normalised byspironolactone, either alone or in combinationwith an ACE-I.84 In cultured aortic endothelialcells, reduced Mg2+ concentration of culturemedium is associated with increased oxidant pro-duction and reduced intracellular glutathione, anantioxidant reserve consumed in neutralisingoxi/nitrosative stress.75 Abnormal Mg2+ homeosta-sis could represent the underlying pathophysio-logical basis for endothelial dysfunction seen ineither PAL or SAL.

Central actions of aldosterone Additional sites of action of ALDO that fall outsideof its classic target tissues include the centralnervous system, where ALDO receptors are foundat diverse sites, including epithelial cells of thechoroid plexus. In this connection, a role forALDO in the genesis of idiopathic intracranialhypertension (IIH) has been proposed, given thereported association between IIH with PAL andSAL85,86 and the prevalence of headache amongpatients with PAL.26 That this proposition does notapply to all patients with IIH is underscored by itsappearance in patients with adrenal insufficiency,unless ALDO would be produced in situ withinthe central nervous system87 as is now recognisedto be the case for the cardiovasculature.88,89

The choroid plexus,a site of high-affinity ALDOreceptor binding, is involved in the production ofcerebrospinal fluid (CSF) and is a target site forALDO, spironolactone and ouabain, an endoge-nous digitalis-like substance released by theadrenals and the hypothalamic-pituitary axis.90-99

ALDO exerts its biologic actions on epithelial cellsby enhancing the activity and number of Na, KATPase pumps in their apical membrane. Aouabain-sensitive Na, K ATPase is present in themicrovilli of the plexus and is involved in the reg-ulation of CSF formation and electrolyte composi-tion (e.g., ouabain reduces CSF production).ALDO is present in CSF, where its concentration

correlates with plasma levels. Either the systemicor intracerebroventricular administration of a min-eralocorticoid (ALDO or DOC) is accompanied bya fall in CSF [K+], together with a rise in arterialpressure, without changes in blood volume,cardiac output, plasma catecholamines or vaso-pressin.99,100 This hypertensive response is abro-gated by intracerebroventricular infusion of K+ ora mineralocorticoid receptor antagonist.99,101

ALDO, therefore, has a central action involved inthe regulation of BP, as well as CSF volume andcomposition. Produced locally within the brain,ALDO’s paracrine properties may likewise con-tribute to BP regulation.87

Research by Felder et al.102-104 has broadenedthe perspective of ALDO’s central actions, whichmay contribute to the pathophysiology of CHF.The hypothalamic paraventricular nucleus (PVN),a forebrain site involved in the regulation of extra-cellular volume and sympathetic nerve activity, isgoverned by circulating neurohormones and byeffector signals originating from the brainstem. Inrats with MI induced by coronary artery ligation,the activity of the PVN is increased. Systemic orintracerebroventricular administration of spirono-lactone reduces this activity, improves baroreflexregulation of renal sympathetic nerve activity(albeit in a time-dependent manner) and preventsthe increase in Na+ appetite and decline in urinaryNa+ and H2O excretion that appear in thismodel.102,103 Plasma levels of TNF-α rise progres-sively over weeks 1–3 following MI, a responseabrogated by intracerebroventricular infusion ofspironolactone started 24 hours after coronary lig-ation, suggesting that central ALDO receptor acti-vation is involved in regulating the release of thispro-inflammatory cytokine.104 The cellular sourceof TNF-α, however, remains uncertain and mayinclude central and/or peripheral tissues.

Extra-adrenal aldosterone productionand tissue repairSome 40 years ago,Lockett et al.105-110 reported thatthe beating heart and contracting soleus muscle ofcats were sites of steroid generation; the substanceresembled 18-D-aldosterone.They found this mol-ecule in coronary venous blood and demonstratedits ability to promote renal salt and water reten-tion. These findings lay fallow until the pastdecade, when Takeda111,112 identified the mRNAexpression of ALDO synthase (CYP11B2) andALDO production in rodent vascular tissue.Silvestre and coworkers113 likewise demonstratedthe expression of this enzyme, integral to thebiosynthesis of ALDO, in rodent heart, whereALDO generation was regulated by Ang II, a lowNa+ or high K+ diet, or adrenocorticotropin(ACTH). Subsequently, the expression of thisenzyme was identified in human cardiovasculartissue, where it was localised to vascular smoothmuscle and endothelial cells.112,114 Even morerecently, and in contrast to normal human hearts,ALDO production was reported to be increased inthe failing human left ventricle,based on coronarysinus levels of ALDO that exceed those found in

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the aorta.115 There exists an upregulated expres-sion of CYP11B2 in the left ventricle of the failinghuman heart of diverse aetiological origins.116

Additionally, 11β-hydroxysteroid dehydrogenase,an enzyme critical to maintaining the specificity ofthe mineralocorticoid receptor, given its equalaffinity for mineralo- and glucocorticoids, hasbeen found in human cardiac tissue.117

Following MI in rodents, macrophages andmyofibroblasts involved in tissue repair expressrenin,ACE and Ang II receptors, predominantly ofthe AT1-subtype.118-122 This has implicated locally-produced Ang II at sites of injury in regulating col-lagen turnover, which has been further suggestedby the cardioprotective actions of losartan, an AT1-receptor antagonist, in attenuating fibrous tissueformation at, and remote to, the site MI.123 Locally-produced Ang II is also involved in regulating denovo ALDO production in the infarcted heart,124

which likewise may contribute to tissue repair.Increased expression of ALDO synthase and ALDOtissue levels, together with increased concentra-tions of Ang II, have been observed in non-infarct-ed rat myocardium following coronary artery liga-tion.124,125 Treatment with losartan prevented theseresponses related to de novo ALDO production.Either losartan or spironolactone treatment pre-vented the accompanying accumulation of colla-gen at sites remote to the MI, suggesting theinvolvement of Ang II-driven local ALDO produc-tion in regulating tissue repair. Hayashi et al.126

have reported that ALDO is extracted by the heartfollowing MI, and the transcardiac ALDO gradient(between aorta and coronary sinus) is correlatedwith coronary venous effluent levels of a serolog-ical marker of collagen turnover (procollagen typeIII aminoterminal peptide, PIIINP) that has beenassociated with LV dilatation and poor functionand prognosis. ALDO is extracted by the chroni-cally failing human heart of diverse aetiologicalorigins, a response blocked by spironolactone.127

Under circumstances in which circulating ALDO isnot increased, spironolactone attenuates neointi-mal thickening following vascular barotrauma,128

tissue repair at sites of fibrous tissue formation129

and vascular injury in stroke-prone rats.130 Theseobservations further suggest that auto/paracrineproperties of locally-produced ALDO participatein tissue repair.

Future directionsSince its discovery some 50 years ago, ALDO haswell-established importance in clinical medicine,including its role in CHF. The past decade has wit-nessed a resurgence of interest in this theadrenal’s most potent mineralocorticoid, as has itsde novo production through steroidogenesiswithin the cardiovasculature and brain. An ever-expanding role for this steroid molecule in themetabolism of mono- and divalent cations byepithelial and non-epithelial cells has warrantedan even broader perspective of its portfolio ofactions. The many peripheral and central actionsof ALDO that can contribute to the pathophysiol-ogy of the CHF syndrome remain to be defined.

This is no more evident than in the adverse struc-tural remodelling of the heart and systemic organsthat accompanies chronic elevations in plasmaALDO (inappropriate relative to dietary Na+) andwhich may be secondary to PBMC activationinduced by [Mg2+]i depletion and transduced byoxi/nitrosative stress. Molecular mechanismsinvolved in immune cell responses remain to beelucidated. Today’s technologies will permit anassessment of ALDO’s role in altering the molecu-lar phenotype of these immune cells, specificallytheir transcriptome and proteome. Such insightsmay provide for the development of serologic bio-markers that address the risk, onset and progres-sion of vascular injury in CHF and could lead theway toward refined and even newer drug targets.

AcknowledgementThe editorial assistance of Richard A. Parkinson,MEd is appreciated.

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toward a broader understanding of aldosterone in congestive heart failure

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