Aldosterone in Congestive Heart Failure

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MECHANISMS OF DISEASE

N Engl J Med, Vol. 345, No. 23

December 6, 2001

www.nejm.org

1689

Review Article

Mechanisms of Disease

LDOSTERONE

ONGESTIVE

EART

AILURE

ARL

T. W

EBER

, M.D.

From the Division of Cardiovascular Diseases, Department of Medicine,University of Tennessee Health Science Center, Rm. 353 Dobbs ResearchInstitute, 951 Court Ave., Memphis, TN 38163, where reprint requestsshould be addressed to Dr. Weber.

LDOSTERONE was isolated from blood andurine, its adrenal origin elucidated, and itssteroid structure identified nearly 50 years ago. Actions involving the reabsorption of sodium andthe release of potassium by epithelial cells in the kid-neys, intestine, and sweat and salivary glands led toits designation as a mineralocorticoid. The physiolog-ic importance of aldosterone in preventing the lossof salt and water during periods of dietary sodiumdeprivation is now clear. Its contribution to the re-tention of sodium in patients with congestive heartfailure, cirrhosis, and the nephrotic syndrome has alsobeen established.

1-3

The perception of its pathophys-iologic importance in congestive heart failure, how-ever, was minimized during the past 20 years, in partbecause of the introduction of angiotensin-convert-ing–enzyme (ACE) inhibitors and their presumptiveelimination of angiotensin II, a major determinant of aldosterone production by the adrenal glands. Recentevidence has revived interest in aldosterone and itsrole in congestive heart failure.

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THE RENIN–ANGIOTENSIN– ALDOSTERONE SYSTEM

Evolution to terrestrial life meant leaving behindthe sea and its continuous source of salt and water. Water on land, when available, was fresh, and there-fore adaptation to land necessitated the developmentof mechanisms to preserve salinity. An internal sourceof salinity is provided by extracellular fluid. Each ar-terial pulse of blood to exchange vessels of the mi-crocirculation represents an onrushing saline tide thatmaintains a dynamic equilibrium with extracellularfluid. Animals living on land had to become capableof preserving their internal environment, includingmaintaining osmotic balance and salinity under a wide range of conditions over which they had little control. Kidneys became responsible for regulatingthe balance of salt and water

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by conserving bothduring periods of deprivation and excreting a diluteurine when water consumption was high. These ad-aptations required a concentrating and diluting mech-anism and were accomplished with the appearance of the loop of Henle. Glomerular filtration in mammals would be maintained within a narrow range despitemodifications in the volume and composition of thefiltrate. Toward this end, kidneys require a plentifulsupply of blood. Renal function is therefore depend-ent on an adequate cardiac output, of which 25 per-cent will normally be apportioned to the kidneys. Thisdependence of renal function on cardiac output ex-plains the vulnerability of patients with heart failure toabnormal renal function, including reduced excretionof salt and water. In heart failure, a competition arisesbetween organs for reduced systemic blood flow. It isparticularly evident during exercise, when the vasodi-lation that appears in working skeletal muscle deprivesthe kidneys of some of their accustomed blood flow.Normal regulation of salt and water homeostasisin mammals involves various sensors and controls op-erating in a negative-feedback loop. These includesensors of renal perfusion and tubular sodium deliv-ery present within the kidney and effector hormoneselaborated by endocrine organs. Key among themare renin, released by the juxtaglomerular cells liningafferent renal arterioles and neighboring macula den-sa cells of the distal tubule,

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and aldosterone pro-duced by the adrenal glands (Fig. 1). Renin cleavesfour amino acids from circulating angiotensinogen,the angiotensin-peptide precursor produced by theliver, to form angiotensin I, a biologically inert dec-apeptide. Angiotensin-converting enzyme, which isbound to the plasma membrane of endothelial cells,cleaves two amino acids from angiotensin I to formangiotensin II. Angiotensin II has several importantactions integral to maintaining circulatory homeosta-sis, including promoting the constriction of the ar-terioles within the renal and systemic circulations andthe reabsorption of sodium in proximal segments of the nephron. It also stimulates the adrenal cortex tosecrete aldosterone, which promotes the reabsorptionof sodium (in exchange for potassium) in distal seg-ments of the nephron and in the colon and the sal-ivary and sweat glands. From a teleologic perspective,the evolution of the renin–angiotensin–aldosteronesystem was a delayed event necessitated by periodsof salt deprivation or the loss of salt and water andthe need to retain them.

Variations in renin secretion occur in response to variations in intake of sodium and water; renin se-

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N Engl J Med, Vol. 345, No. 23

December 6, 2001

www.nejm.org

The New England Journal of Medicine

cretion is inhibited when salt and water are taken inand activated when they are not.

There can there-fore be periodicity to the activation of this systemthroughout a given day, depending on the frequency of food intake, or over the course of many days, whenperiods of starvation alternate with the consumptionof food and water. The reductions in renal perfusionthat normally occur with the assumption of an up-right posture and during ambulation also stimulaterenin secretion.

The renin–angiotensin–aldosterone system pre-serves circulatory homeostasis in response to a lossof salt and water, such as that which can occur withintense and prolonged sweating caused by high am-bient temperatures, vomiting, or diarrheal illness. Plas-ma concentrations of the system’s effector hormonesrise quickly in response to a contraction of intravas-cular volume and a reduction in renal perfusion. An-giotensin II is the principal stimulator of aldosteroneproduction when intravascular volume is reduced.

1,13

Potassium is also a major physiologic stimulus toaldosterone production; aldosterone secretion is in-tegral to potassium homeostasis because aldosteronehas the ability to increase potassium excretion in urine,feces, sweat, and saliva.

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Aldosterone thereby servesto prevent hyperkalemia during periods of high po-tassium intake. For example, aldosterone secretion ris-es after the consumption of foods high in potassiumcontent or after vigorous physical activity that causesthe release of potassium from skeletal muscle. The im-

Figure 1.

The Renin–Angiotensin–Aldosterone System.Angiotensinogen, the precursor of all angiotensin peptides, is synthesized by the liver. In the circulation it is cleaved by renin, whichis secreted into the lumen of renal afferent arterioles by juxtaglomerular cells. Renin cleaves four amino acids from angiotensino-gen, thereby forming angiotensin I. In turn, angiotensin I is cleaved by angiotensin-converting enzyme (ACE), an enzyme bound tothe membrane of endothelial cells, to form angiotensin II. In the zona glomerulosa of the adrenal cortex, angiotensin II stimulatesthe production of aldosterone. Aldosterone production is also stimulated by potassium, corticotropin, catecholamines (e.g., norep-inephrine), and endothelins.

OOOHO

AngiotensinogenAngiotensin IAngiotensin IIAldosteroneACERenin

MECHANISMS OF DISEASE

N Engl J Med, Vol. 345, No. 23

December 6, 2001

www.nejm.org

1691

portance of aldosterone in potassium homeostasis ismost evident in patients with aldosterone insufficien-cy (Addison’s disease), in whom hyperkalemia is com-mon and can be reversed by treatment with a min-eralocorticoid.

Further evidence of the importance of potassiumas a stimulus to aldosterone production comes fromstudies in genetically manipulated mice that do notexpress the angiotensin precursor angiotensinogenand therefore have little or no angiotensin II.

Inthese animals, dietary sodium deprivation causes hy-perkalemia, which, in turn, increases aldosterone se-cretion, thereby stimulating the reabsorption of saltand water and maintaining extracellular fluid volume.Restriction of both dietary sodium and potassiumleads to hypotension and death in these animals.In addition to their individual effects on salt and water homeostasis, angiotensin II and aldosteronehave other endocrine actions relevant to the mainte-nance of circulatory homeostasis. They contribute tothe coagulation of blood, in part through the in-creased production of plasminogen-activator inhibitortype 1 and the aggregation and activation of plateletsat sites of bleeding

; they constrict systemic arteriolesto preserve arterial pressure in the face of contrac-tion of the intravascular volume

; and they stimu-late thirst.

Angiotensin II and aldosterone are also involvedin regulating inflammatory and reparative processesthat follow tissue injury.

19,20

In this capacity, they stim-ulate cytokine production, inflammatory-cell adhesion,and chemotaxis; activate macrophages at sites of re-pair

; and stimulate the growth of fibroblasts and thesynthesis of type I and III fibrillar collagens, whichgovern the formation of scar tissue.

A substance produced by cells within a tissue canexert actions on the same or different cells; these ef-fects are known, respectively, as autocrine and para-crine properties. Recent studies have demonstratedthe presence of aldosterone synthase messenger RNA (mRNA) and its activity together with aldosteroneproduction by endothelial and vascular smooth-mus-cle cells in the heart and blood vessels (Fig. 2).

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Once considered the sole province of the zona glom-erulosa of the adrenal glands because of the key en-zymes involved in its steroidogenesis, the productionof aldosterone by the heart is regulated by angioten-sin II and by modifications in dietary sodium andpotassium. The physiologic importance of locally pro-duced aldosterone is not known, but early findingssuggest that it may contribute to tissue repair aftermyocardial infarction.

ALDOSTERONE AND THE PATHOPHYSIOLOGY OF CONGESTIVE HEART FAILURE

Some 60 years ago, both urine and plasma frompatients with congestive heart failure were found tocontain a substance with sodium-retaining activity

;this discovery drew attention to the role of the kidney in the pathogenesis of congestive heart failure. It soonbecame evident that the initial stages of heart failureinvolve an expansion of intravascular volume and weight gain that averts volume depletion when relent-less salt and water retention produces extravascular volume expansion (e.g., edema). Subsequently, stud-ies of renal hemodynamics revealed marked reduc-tions in renal blood flow with a less severe decline inglomerular filtration and a preserved or even increasedfiltration fraction.

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The retention of sodium is ev-ident not only in urine but also in feces, sweat, andsaliva, indicating a widespread avidity for sodium. Thesalt-active substance mediating many of these changes was initially named electrocortin, but because of its18-aldehyde steroid structure and adrenal origin it waslater renamed aldosterone.

In heart failure, the pres-ence of increased amounts of aldosterone in urine andplasma correlates with the retention of sodium and water at renal and extrarenal sites.In normal subjects whose diet contains a normalamount of sodium, the aldosterone secretion rate is100 to 175 µg (277 to 485 nmol) per day; in pa-tients with congestive heart failure, the aldosteronesecretion rate may be as high as 400 to 500 µg(1100 to 1400 nmol) per day.

Values for plasma al-dosterone are in the range of 5 to 15 ng per deciliter(139 to 416 pmol per liter) in normal subjects whosesodium intake is normal and may reach 300 ng perdeciliter (8322 pmol per liter) in patients with con-gestive heart failure — a concentration similar to thatin normal subjects whose sodium intake is severely restricted.

Aldosterone secretion in patients withcongestive heart failure is regulated by several majorstimuli. These include angiotensin II and elevationsin serum potassium concentrations. In normal subjects, corticotropin is thought to play a short-lived,permissive role in stimulating aldosterone production.However, in patients with congestive heart failure,plasma corticotropin concentrations may be chronical-ly increased, resulting in high plasma cortisol concen-trations and contributing to the increase in aldoste-rone secretion.

Minor stimuli, which may take onadditional importance in patients with congestive heartfailure, include circulating catecholamines, endothe-lins, and arginine vasopressin.Decreased metabolic clearance of aldosterone by the liver further contributes to increased plasma con-centrations of aldosterone in patients with congestiveheart failure. In normal subjects, hepatic aldosteroneclearance is complete within one passage through theliver, so that little or no aldosterone is found in he-patic venous plasma. Because of the reduced hepaticperfusion in patients with congestive heart failure,aldosterone clearance is also reduced; this problemis exacerbated by upright posture and ambulation.This reduction can account for a severalfold increase

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