Endocrine factors in congestive heart failure

Endocrine

Factors Heart

in Congestive

Failure*

JACQUES GENEST, M.D., PIERRE GRANGER, M.D., JACQUES DE CHAMPLAIN, and ROGER BOUCHER, M.D. Montreal,

M.D.

Canada

T

HERE IS impressive evidence that patients with congestive heart failure fail to excrete sodium and lack ability to maintain sodium balance. The evidence is both clinical and experimental. First, it is a basic clinical fact that a diet severely restricted in sodium will improve the condition of patients with congestive heart failure and that salt loads will aggravate it. Braunwald et al. l have recently devised a sodium tolerance test that clearly demonstrates the inability of patients with congestive heart failure to excrete a salt load. Similar findings were observed by Barge? in dogs with congestive heart failure induced experimentally by pulmonary stenosis and tricuspid insufficiency. Tricuspid insufficiency alone in dogs produced a rise in right atria1 pressure with definite al.terations in sodium excretion but without signs of congestive heart failure. However, the combination of tricuspid insufficiency and pulmonary artery stenosis in dogs results in a state of congestive heart failure similar to that seen in man with failure to excrete salt In such an animal preparation, an inloads. fusion of 3.5 per cent sodium chloride solution directly into one renal artery produces no rise in sodium excretion, in contrast to the findings in similar experiments, performed in a normal dog. This failure of sodium excretion occurs without any change in the rate of glomerular filtration. These findings are convincing evidence of the increased tubular rea.bsorption of sodium in dogs with congestive heart failure. Second, a normal rate of glomerular filtration has been found in a number of patients with frank congestive heart failure.3s4 Bradley and Blake4 emphasized the absence of any significant

change in this rate in many patients during or after recovery from congestive heart failure. They pointed out that in some patients the rate of glomerular filtration even fell during recovery without in any way preventing the diuretic response to therapy. It should also be recalled that in many cases of parenchymatous renal diseases, such as nephrosclerosis, pyelonephritis or glomerulonephritis, the rate of glomerular filtration may be extremely low without any evidence of edema formation. These observations again indicate the importance of increased tubular reabsorption of sodium in the pathogenesis of edema in congestive heart failure. Third, many investigators have emphasized the low concentration of sodium in the urine, sweat and saliva of patients with congestive heart failure, thereby indicating the presence of increased mineralocorticoid activity in the blood. Fourth, detailed studies of renal hemodynamics and of urinary excretion of sodium have shown that even when the total amount of sodium presented at the proximal tubules is greatly decreased because of the low glomerular filtration rate (even in the presence of a high filtration fraction), there is fundamentally a markedly increased tubular reabsorption of sodium.3 This finding is in accord with the beneficial effects of natriuretic agents, such as the thiazides, the mercurials, spironolactone and others, which are particularly active at the distal tubule level. These natriuretic agents, with or without marked restriction of dietary sodium, can completely relieve the edema of congestive heart failure yet have no known direct effect on the heart. If edema in congestive heart failure is merely a disturbance in circulatory hemodynamics, it is

* From the Clinical Research Institute and the HBtel-Dieu Hospital, Montreal, Canada. Address for reprints: Jacques Genest, M.D., 110 Avenue des Pins ouest, Montreal, Canada. VOLUME

22,

JULY

1968

35

Genest et al.

36

difficult to understand how the natriuretic agents would be helpful if they acted on the kidneys alone. Fifth, lack of edema and failure to retain sodium have been observed in patients with true renovascular hypertension or with stenotic lesions of one or both renal arteries with markedly decreased glomerular filtration rate and renal blood flow. Similar observations have been made in animals in which the rate of glomerular filtration was decreased by more than 75 per cent and there was no edema. The disturbances in renal hemodynamics, the proteinuria and cylindruria observed in many patients with advanced congestive heart failure are only temporary. These functional changes rapidly return to normal after relief of the In addition, there is very little histoedema. logic evidence of renal damage in the kidneys of patients with congestive heart failure. The critical and wise observations of Bradley and Blake4 and Burch and Ray5 emphasized the importance of a combination of increased renal venous pressure and of intrarenal arterial constriction for the production of edema in congestive heart failure, although they gave no evidence on how these combined mechanisms operate to produce edema. The evidence we have described reveals that the cardiac lesion is the initiating and the “sine qua non” factor in the syndrome of congestive heart failure, but the kidney is ultimately responsible for the increased tubular reabsorption of sodium in response to metabolic and hormonal Therefore, we will (1) review in greater factors. detail the recent findings related to aldosterone and to the renin-angiotensin system and (2) describe the results of some preliminary experiments on how changes in the right atria1 pressure in dogs affect renal venous renin activity. It is worthy of emphasis that there is no definite evidence that the mechanisms leading to edema are identical in all instances of congestive heart failure, whatever its origin-valvular lesions, hypertensive disease, arteriosclerotic heart disease, constrictive pericarditis, or primary disease of the lungs with pulmonary hypertension. THE

RENIN-ANGIOTENSIN-ALDOSTERONE

NORMAL

SYSTEM

PHYSIOLOGY

is an enzyme liberated by the juxtaglomerular granular cells mostly in response to a decrease in blood volume, a decreased renal perfusion pressure, depletion and restriction of salt, Renin acts on an alpha 2and upright posture. I&in

globulin substrate to yield a decapeptide, angiotension I, with no precise biologic activity (Fig. 1). A converting enzyme present in plasma splits two terminal amino acids from angiotensin I to yield an octapeptide, angiotensin II, which not only has a potent vasopressor effect and acts on the renal tubular reabsorption of sodium but is the most direct and important stimulus of aldosterone secretion. EXTRA-SPLANCHNIC CLEARANCE

RENIN I

ANGIOTENSIN II Ii&

4 Y.C.R. 0 l-n

LIVER7

T

HEPATICBLCW FLCW RATEOFEXTRACTION

35‘3%TETRlHYDRd

HALF-LIFE' Na

Figure 1.

IN SWEAT SALWA “RIM

The renin-angiotensin-atdosteronesystem.

Aldosterone is secreted by the zona glomerulosa of the adrenal cortex at the rate of 50 to 175 pg./ day in humans. Its plasma level, normally between 2 to 15 ng./lOO ml. of plasma, is governed by the amount secreted per day and the rate of removal from plasma. Since free aldosterone is excreted in the proportion of only 0.2 per cent, the urinary excretion does not affect plasma levels. The major urinary metabolites of aldosterone are the acid-labile 18-oxoconjugate (7 per cent) and the tetrahydroaldosterone glucuronide (35 per cent) (Fig. 1). In many instances, the regulation of the plasma level of free aldosterone is affected in greater part by the rate of removal of this hormone, which occurs mostly in the liver and to a certain extent in extrasplanchnic sources (12 to 15 per cent). Bougas and Tait et al .6,7 have shown that approximately 95 to 97 per cent of aldosterone in plasma is removed through one passage through the liver and that this rate of extraction is closely dependent on the hepatic blood flow. The metabolic clearance rate of aldosterone averages 2,400 liters of blood per day. Therefore, any decrease in the hepatic blood flow, such as that produced by upright posture or by passive congestion of the liver, will have a major effect on the plasma levels of free aldosterone. Another important factor is the rate of inactivation of aldosterone by liver cells, since Yates et al.* have shown that in passive congestion of the liver, there is a profound decrease in the rate of reduction of the A4 group of ring A and, therefore, in the inactivation of aldosterone into the tetrahydro-aldosterone glucuronide. THE AMERICAN

JOURNAL

OF CARDIOLOGY

Endocrine IN CONGESTIVE

HEART

Factors

FAILURE

Increased Renin-Angiotensin Act&y: In 1946, Merrill et al9 demonstrated an increased vasoconstrictor activity of renal venous blood in 8 of 11 patients with chronic congestive heart failure. This increased activity was presumed to be due to augmented renin concentration. In 1963, de Champlain, Bouc:her and Genest,‘O using Boucher’s procedure for measuring arterial angiotensin levels, reported very high levels of arterial angiotensin in 13 of 14 patients with congestive heart failure (Fig. 2). In addition, renin activity was found to be greatly increased in all of 5 cardiac edematous patients. The mean arterial angiotensi-n levels in the 14 patients studied decreased from 205 ng./lOO ml. of plasma to 49, after total or partial relief of edema by digitalis, sodium restriction, administration of natriuretic agents, singly or in combination. It must be stressed that the effects of severe sodium NORMAL SUBJECTS

ANGIOTENSIN

200

rgrL/min.

xx)

PLASMA RENIN ACTIVITYm

I

0 1-I

9.3~1

WOWOTENSIVE ‘+WERTENSIVE *

PAufI*L

COMGESTIVE

PATIENTS l

on TOTAL

2. Results of arterial plasma angioteruin and peripheral blood renin activity in patients with congestive heart failure before and after partial or total relief of their edema.

Figure

in Heart

Failure

37

ease admitted to the hospital with subacute pulmonary edema and anasarca are illustrated in Figure 4. The arterial angiotensin level was 850 ng./lOO ml. of plasma before treatment. Digitalization, restriction of the sodium intake to 10 mEq./day and natriuretic agents for six days resulted in the loss of 8 kg. in body weight and a fall of the angiotensin concentration to 220 ng. On the fifteenth day of treatment, sudden neurogenie shock developed, with a fall in systolic blood pressure to 70 mm. Hg and acute pulmonary edema. At that moment, the arterial angiotensin rose to 400 ng. On the twentyeighth day of treatment the patient had lost 19 kg. in weight, and arterial angiotensin had returned to normal level. With the exception of the episode of shock, the patient was normotensive despite the very high levels of arterial angiotensin. A correlative study of sodium balance, peripheral blood renin activity, arterial angiotensin and urinary aldosterone is illustrated in Figure 5. In this case a 55 year old patient was admitted to the hospital with anasarca and subacute pulmonary edema secondary to congestive heart failure. Before treatment, peripheral blood renin activity was 300 ng. of angiotensin liberated per liter of plasma per minute, and arterial angiotensin was 61 ng. per 100 ml. of plasma. To study the effect of abdominal pressure on renin activity, a paracentesis of 2 liters was performed, but it failed to modify the level of peripheral bloodrenin activity. Urinary aldosterone was 30 pg./ day (normal 2 to 12). After digitalization, restriction of sodium intake to 17 mEq./day and administration of furosemide (80 mg./day), there was a progressive loss of edema; peripheral blood renin activity and arterial angiotensin rapidly decreased to undetectable levels and urinary aldosterone to normal range. During this study, the patient had lost 20 kg. in weight, and his blood pressure was at no time increased above normal levels. The severe sodium restriction

RENIN ACTIVITY

restriction or depleuon, or both, were completely opposite to those obsserved in normal subjects or in patients with essential hypertension submitted to the same stimulus (Fig. 3). The patients with congestive heart failureresponded tosodium restriction and depl!etion by a fall in renin activity, arterial angiotensin and aldosterone secretion or excretion.” Studies made of a patient with mitral valvular dis-

VOLUME

22,

JULS

1968

ALDOSTERONE

NORMAL SUBJECTS PATIENTS E ESSENTIAL HYPERTENSION

CONGESTIVE CARDIAC FAILURE

4

+

t

1

Figure 3. Effect of smre sodium retention and depletion in normal subjects and in congestive heart failure.

Genest et al.

38

NEUROGENIC SHOCK

t ACUTE PULM. EDEMA t SYST ER : 70mmHg

__ . Inn-l

Figure 4.

Ejects of restriction of dietary sodium and administration of natriuretic agent on body weight

and arterial angiotensin levels in a 58 year old patient with severe congestive heart failure.

IO

-e

500mg

CHLOROTHIAZIDE

SPIRONOLACTONE A A A u

HYDROCHLOROTHIAZIDE

NoINTAKE

I

*

loorng i.v. MTHEOPHYLLINE-500mg

"NR 0

DIGITALIZED

1’

I

6

‘1

I

I2

“I”

IJOmg

18

1 “I

24

i.v.

30

DAYS

and depletion produced in this patient, as in other similar cases, a response of renin activity, arterial angiotensin and aldosterone completely opposite to that of a normal subject submitted to the same treatment. A third example is that of a 66 year oldpatient with congestive heart failure secondary to mitral valvular disease (Fig. 6). This patient was cyanotic, had numerous rales over both lung bases, pitting edema over both legs and the sacral region. The peripheral plasma renin activity and the arterial angiotensin levels measured before treatAfter severe restriction ment were quite high. of sodium to 10 mEq./day and administration of quinethazone the patient rapidly lost his edema, and both peripheral plasma renin activity and arterial angiotensin levels decreased to undetectable levels. Of the 14 patients studied, the congestive heart failure was secondary to hypertensive cardiovascular disease in only 3. It is of interest that the 11 other patients were normotensive in spite of the very high levels of peripheral plasma renin activity and of arterial angiotensin. Despite the Aldosterone Secretion and Excretion: high activity of the renin-angiotensin system, aldosterone secretion or excretion has been found within normal range in about 50 per cent of patients in various phases of congestive heart fail-

ure. Wolff et all2 found normal excretion in most patients with left-sided failure and high values in the majority of patients with right-sided More recently, Luetscher et a1.13J4 refailure. ported that aldosterone secretion rate was within normal range in 6 of 7 cardiac patients whose circulation was considered “relatively normal by clinical and laboratory examinations.” However, they found high secretion rates in 4 of 6 paThey also tients with congestive heart failure. observed that patients with severe congestive heart failure have a decreased renal clearance of the acid-labile, 18-0~0 metabolite associated with higher circulating levels of this compound. The failure of adequate response of aldosterone secretion to high levels of angiotensin has not yet been exThe recent finding of Kloppenborg et plained. a1.15 that angiotensin infusions given to patients with congestive heart failure had little or no effect on aldosterone secretion, either before or after diuretic therapy is of great interest and is consistent with these observations. Rates of aldosterone secretion in dogs with experimental failure of the right side of the heart secondary to pulmonary artery stenosis and tricuspid insufficiency were found by Davis et al. 16-20 to be several times higher than in normal dogs. In such animals, sodium retention is almost complete. THE

AMERICAN

JOURNAL

OF CARDIOLOGY

Endocrine Factors in Heart Failure ABDOMINAL

39

PARACENTESIS

“r’“r’

WEIGHT Kg%,I

“\I

60 mEq/DAY

5. Metabolic J&dies of the effects of dietary changes of sodium intake and administration of furosemide on body weight, urinary

J

Figure

URINARY

excretion, sodium peripheral plasma renin activity, arterial angiotensin levels and urinary aldosterone excretion (measured by the physicochemical method of Nowaczynski et al.) in a 55 year old man with congestive heart failure.

ANGIOTENSIN 61 ng/lOOml ARTERIAL BLOOD p/DAY

I

I

300

39

0

0

0

40

URINARY

ALOOSTERONE

According to Laragh et al.,‘Ji administration of salt loads to patients with congestive heart failure leads to a paradoxic increase in aldosterone secretion. Aldosterone Mettzbolism: Due to the elegant work of Tait6,7 and Luetscher13J4 and their collaborators a clearer picture of aldosterone metabolism has emerged in the last few years, although it appears to be much more complex. Direct measurements of levels of free aldosterone in plasma or their indirect determination from the values of the secretion rate and the metabolic clearance rates of aldosterone have shown that these levels are increased in most patients with congestive heart failure.? This increase is due mainly to a decreased clearance rate secondary to a fall in hepatic blood flow caused by the passive congestion of the liver and to a decreased rate of extraction and inactivation of aldosterone by the liver cells. In patients with moderate cardiac disability, hepatic extraction of aldosterone is nearly complete, whereas in those with advanced congestive heart failure, the reduction in the metabolic clearance rate of aldosterone is due in good part to a fall in the rate of removal of aldosterone by the liver cells. This rate may be as low as 50 to 75 per cent, compared to 95 to 97 per cent in normal subjects.r3J4 Tait and COworkers’ have alsdgiven recent evidence that the VOLUME

22,

JULY

1968

o

3

extrasplanchnic clearance of aldosterone is decreased in congestive heart failure. These findings are reflected by the high levels of free aldosterone in plasma and by a markedly increased mean half-life of aldosterone, as shown by Tait et a1.7 and Wolff et a1.22’23in humans and by Davis and Ayers et a1.i6J7*i8 in dogs with congestive heart failure secondary to pulmonary No

INTAKE

IDnEq/D.

NATRIURETIC iDUlNETHAIONE

WEIGHT

PLASMA

RENIN

50mg

17

VW

v 7 1

LOSS

20

ACTIVITY lng/L/ain)

0I OAYS

Figure

1

4

1

10

l3

6.

Effects of severe dietary sodium restriction and administration of a natriuretic agent on body weight, periph-

eral plasma renin activity and arterial angiotensin levels in a 66 year old woman with marked edema secondary to congestive heart failure who was receiving digitalis.

Genest

40

The artery stenosis and tricuspid insufficiency. mean half-life of H3-d-aldosterone in cardiac patients with edema is 46 min. compared to 33 in healthy volunteers. W01ff%~ had reported high plasma levels in 4 of 5 patients with active sodium retention and progressing edema, whereas normal levels were found in most cardiac paThese high levels tients with stationary edema. of plasma aldosterone are therefore responsible for the observed very low sodium excretion in the urine, sweat and saliva of patients with congestive heart failure and progressing edema. ANTIDIURETIC HORMONE ACTIVITY IN CONGESTIVE HEART FAILURE Understanding of this aspect of the mechanism of cardiac edema has been confused by conflicting reports of antidiuretic hormone activity in the urine or plasma of patients with congestive heart failure. Indirect evidence that the antidiuretic hormone may not be essential for the formation of edema in congestive heart failure has been provided by Hamilton et a1.,z4 who showed that severe sodium retention and ascites formation persisted in dogs with thoracic caval constriction despite injury to the neurohypophysis and proThe reverse exduction of diabetes insipidus. periment was performed by Laragh and coworkers,2j who produced a state of diabetes insipidus by destroying the posterior pituitary and subsequently showed that the constriction of the thoracic inferior vena cava resulted in severe sodium retention and ascites formation. RELATION OF RIGHT ATRIAL PRESSURE TO RENAL VENOUS RENIN ACTIVITY From our present knowledge of the physiologic factors regulating the release of renin by the juxtaglomerular cells, it is apparent that none of the factors known to stimulate renin could adequately explain the high peripheral renin activity and arterial angiotensin levels observed. Since one of the earliest and most reliable signs of congestive heart failure is increased venous pressure, we have set up an experimental protocol in dogs to study the effects of changes in right atria1 Monpressure on renal venous renin activity. grel dogs are anesthetized with intravenously administered Nembutal@ (30 mg./kg.), and two catheters are introduced through the right external jugular vein, one with an inflatable balloon and the other one for recording right atria1 pressure. Two additional catheters are also introduced into the lower inferior vena cava and guided by hand into the right and left renal

et al. \;eins, respectively (Fig. 7). After a control period, the balloon is inflated by injection of water and placed so as not to obstruct the flow of the inferior or superior vena cava; the right atria1 pressure is monitored, and simultaneous samplings of blood from both renal veins are obtained at various intervals during the periods of higher right atria1 pressure as well as before inflation and after deflation. Increasing the right atria1 pressure twofold, as illustrated in Figure 8, resulted in an almost twofold increase in blood renal venous renin activity. After deflation and return of the atria1 pressure to control levels, renal venous renin activity decreased rapidly to its pre-inflation levels. In a second experiment, illustrated in Figure 9, the pressure was increased and decreased progressively. The stimulus appeared to be short-lived, in terms of the response of the renal venous renin activity, but was similar to that found in the previous dog. These very preliminary experiments suggest that a rise in right atria1 pressure may produce, by ways undetermined at present, an increase in renal venous renin activity. It is possible that this increase is due to a decreased renal blood flow and to the secondary increase in renal venous pressure. This has not yet been clarified. If the stimulus originates in the right atrium, it will have to be determined whether the increase in renal venous renin activity is mediated through the nervous system or through other mechanisms. Much work remains to be done before one can evaluate properly the importance of these preliminary findings in the physiopathology of edema formation in congestive heart failure. DISCUSSION Although the theories of forward and backward failure proposed three decades ago to explain the mechanism of edema in congestive heart failure are inadequate, a number of facts have been well established: (1) the effects of upright posture ar.d, therefore, of increased venous pressure on the production of dependent edema ; (2) the effects of exercise with subsequent inability of the heart to increase its cardiac output and the appearance of breathlessness. These are accompanied by a greater oxygen extraction by the tissues, with widening of the arteriovenous oxygen difference; (3) the venous distention and increased venous pressure; and (4) the decreased cardiac output at rest in advanced states of congestive heart failure, with deTHE AMERICAN JOURNALOF CARDIOLOGY

Endocrine

Figure

7.

Factors

in Heart

Experimental

protocolfor the study of the effects of changes in right atria1 pressure on renal ven0uS plasma renin activity.

Failure

41

adrenergic nerves act on the tubular reabsorption of sodium is not known except for the fact that administration of adrenergic blocking agents is followed by natriuresis. Water retention appears secondary to renal retention of sodium, since edema formation and ascites can occur in diabetes insipidus in either man or dog. There is a need to reassess and restudy the mechanisms of congestive heart failure by the simultaneous measurement of hemodynamic,

RIGHTATffAA$RESSURE

Figure

8.

right atria1 venom r&n

E&ts of .:hanges in the pressure on bilateral Note the activity.

acute but temporary rise in renal venous renin activity in both kidneys immediately after the inflation of the balloon in the right atrium and the increase in right atria1 pressure.

OLEFT

0

creased renal blood flow. There is also a decreased glomerular filtration rate and a high filtration fraction due to increased intrarenal most marked at the postvasoconstriction, glomerular afferent arterioles. Hemodynamic factors are not sufficient to explain the formation of edema, yet the evidence for increased mineralocorticoid activity in blood overwhelming. Important advances in is knowledge of the participation of the reninangiotensin-aldosterone system have been made, although the picture is far from being entirely clear. The state of normotension in congestive heart failure not due to hypertensive cardiovascular disease is unexplained in the presence of high peripheral rerin activity and arterial angiotensin levels. The factors that prevent in some patients the marked stimulation of aldosterone secretion by the very high activity of the reninangiotensin system observed are not known. There is a fundamental difference between the response of aldosterone, renin activity and angiotensin to sodium restriction and depletion in patients with congestive heart failure and the response in normal subjects submitted to the same stimuli. How intrarenal vasoconstriction and VOLUME

22, JULY

1968

’

*

30

60

90

l33i;ATRIAL

120 TIME IYIN.

2lO

240

RENIN ACTIVITY m RlGHT OLEFT

1

0

180

PRESSURE

fW~)i_J“?$XlS

0

150

20

40

Rf

NAL

"

VflN

"

60 80 TIME (MINJ

IO0

120

140

Figure mm

9. Effects of progressive changes in right atria1 firesRight atria1 on bilateral renal venous renin activity.

pressure was raised by inflating atrium.

a balloon

in the right

42

Genest

hormonal and metabolic parameters at rest and during exercise in carefully selected patients in whom the phase and state of congestive heart failure have been precisely defined. The complexity of aldosterone metabolism makes it necessary to measure simultaneously the rate of secretion, urinary excretion, the rate of metabolic clearance and plasma levels. Only through close teamwork can significant advances be made in the study of the mechanism of cardiac edema. CONCLUSION Evidence for increased mineralocorticoid activity in congestive heart failure has been pre-

et al.

10.

11.

12.

13.

Findings on the increased activity of the sented. renin-angiotensin-aldosterone system have been reviewed. Preliminary experiments suggest that increasing the right atria1 pressure results in a temporary rise in renal venous renin activity.

14.

REFERENCES

15.

1. BRAUNWALD,E. and collaborators.

Congestive heart failure. Biochemical and physiological considerations. Combined clinical staff conference, National Institutes of Health. Ann. Znt. Med., 64, 904, 1966. 2. BARGER, A. C. The pathogenesis of sodium retenin congestive heart failure. !@etabolism, 5: 480, 1956. 3. SINCLAIR-SMITH,B., KATTUS, A. A., GENEST, J. and NEWMAN, E. V. The renal mechanism of electro-

16.

tion

lyte excretion and the metabolic balances of electrolytes and nitrogen in congestive cardiac failure; the effects of exercise, rest and aminophylline. Bull. Johns Hopkins Hosp., 84: 369, 1949.

4. BRADLEY, S. E. and BLAKE, W. D. Pathogenesis of renal dysfunction during congestive heart failure. Am. J. Med., 6: 470, 1949. 5. BURGH, G. E. and RAY, C. T. The consideration of the mechanism of congestive heart failure. Am. Heart J., 41: 918, 1951. 6. BOUGAS, J., FLOOD, C., LITTLE, D., TAIT, J. F., TAIT, S. A. S. and UNDERWOOD, R. Dynamic aspects of aldosterone metabolism. In: Aldosterone: A Symposium, p. 25. Oxford, England, 1964. Blackwell Scientific Publications. 7. TAIT, J. F., BOUGAS, J., LITTLE, B., TAIT, S. A. S. and FLOOD, C. Splanchnic extraction and clear-

17.

18.

19.

20.

21.

22. 23.

ance of aldosterone in subjects with minimal and marked cardiac dysfunction. J. Clin. Endocrinol.,

25: 219, 1965. 8. YATES, T. E., URQUHART, J. and HERBST, A. L. Impairment of the enzymatic inactivation of adrenocortical hormones following massive venous congestion of the liver. Am. J. Physiol., 194: 65, 1958. 9. MERRILL, A. J., MORRISON, J. L. and BRANNON, E. S. Concentration of renin in renal venous blood

24.

25.

in patients with chronic heart failure. Am. J. Med., 1: 468, 1946. DE CHAMPLAIN, J., BOUCHER, R. and GENEST, J. Arterial angiotensin levels in edematous patients. Proc. Sot. Exprr. Biol. &* Med., 113: 932, 1963. GENEST, .I., DE CHAMPLAIN, J., VEYRAT, R., BouCHER,R., TREMBLAY,G. Y., STRONG,C. G., KOIW, E. and MARC-AURFLE, J. Role of the reninangiotensin system in various physiological and pathological states. In: Hypertension, Proceedings of the Council for High Blood Pressure Research, Vol. XIII, p. 97. New York, 1965. American Heart Association. WOLFF, H. P., KOCZOREK,K. R., BUCHBORN,E. and RIEKER, G. Endocrine factors. J. C/won. Dis., 9: 554,1959. LUETSCHER,J. A., CAMARGO,C. A., HANCOCK,E. W., DOWDY, A. J. and NOKES, J. W. Observations of aldosterone metabolism in congestive heart failure. Tr. A. Am. Physicians, 77: 224, 1964. CAMARGO, C. A., DOWDY, A. J., HANCOCK, E. W. and LUETSCHER,J. A. Decreased plasma clearance and hepatic extraction of aldosterone in patients with heart failure. J. Clin. Invest., 44: 356, 1965. KLOPPENBORG,P. W. C., BENRAAD,T. C. and MAJOOR, C. L. H. The secretion rate of aldosterone in patients with heart failure. Acta endocrinol., Suppl. 119, 93, 1967. DAVIS, J. 0. Mechanisms regulating the secretion and metabolism of aldosterone in experimental secondary hyperaldosteronism. Recent Progr. Hormone Res., 17: 293, 1961. DAVIS, J. 0. Adrenocortical and renal hormonal function in experimental cardiac failure. Circululion, 25: 1002, 1962. AYERS, C. R., DAVIS, J. O., LIEBERMAN,S., CARPENTER,C. C. J. and BERMAN,M. The effects of chronic hepatic venous congestion on the metabolism of d-1-aldosterone and d-aldosterone. J. Clin. Invest., 41: 884, 1962. DAVIS, J. 0. Mechanism of salt and water retention in congestive heart failure: the importance of aldosterone. Am. J. Med., 29: 486, 1960. URQUHART, J. and DAVIS, J. 0. Role of the kidney and the adrenal cortex in congestive heart failure. Mod. Coruepts Cardiovas. Dis., 32: 781, 1963. LARAGH, J. H. Hormones and the pathogenesis of congestive heart failure: vasopressin, aldosterone and angiotensin II. Circulation, 25: 1015, 1962. WOLFF, H. P. Aldosterone in congestive heart failure. Acta cardiol., 20: 424, 1965. WOLFF, H. P., LOMMER, T., JAHNECKE, J. and TORBICA, M. Hyperaldosteronism in edema. In Ref. 6, p. 471. HAMILTON, W. F., ELLISON, R. G., PICKERING, R. W., HAGUE, E. E. and RUICKER, J. F. Hemodynamic and endocrine response to experimental mitral stenosis. Am. J. Physiol., 176: 445, 1954. LARAGH, J. H., VAN DYKE, H. B., JACKSON, J., ADAMSONS,K. and ENGEL, S. The experimental production of ascites in the dog with diabetes insipidus. J. Clin. Invest., 35: 897, 1956.

THE AMERICANJOURNALOF CARDIOLOGY