Effect of reducing atrial pressure on atrial natriuretic factor and vasoactive hormones in congestive heart failure secondary to ischemic and nonischemic dilated cardiomyopathy

Effect of Reducing Atrial Pressure on Atrial Natriuretic Factor and Vasoactive Hormones in Congestive Heart Failure Secondary to lschemic and Nonischemic Dilated Cardiomyopathy Mark W. I. Webster, MB, ChB, D. Norman Sharpe, MD, Renee Coxon, RN, Judy Murphy, RN, Sharon Hannan, PhD, M. Gary Nicholls, MD, and Eric A. Espiner, MD

trial natriuretic factor (ANF) is a peptide with natriuretic, diuretic and vasorelaxant properties in animals and man. A physiologic role opposing the renin-angiotensin-aldosterone system has been postulated.’ Evidence for this has emerged from studies of administered synthetic peptide2*3 and, more recently, from the use of specific antisera.4 In man, an acute increase in atria1 pressure with intravenous volume loading5 or during atria1 tachyarrhythmia# is associated with a transient elevation in plasma ANF. Increased levels are found when there is chronic elevation in atria1 pressure, such as with congestive heart failure (CHF)7 or chronic renal failure.8 The highest levels of plasma ANF are usually found in those with the most marked increase of atria1 pressure. 9-11 However, little is known of the magnitude and time course of response to acute changes in atria1 pressure in man, particularly in those with CHF. We examined the effects of an acute and sustained reduction in atria1 pressure on plasma ANF and other vasoactive hormones in patients with CHF.

The effect of an acute and sustained reduction in atrial pressure on atrial natriuretic factor (ANF) and vasoactive hormone secretion was studied in 9 patients with congestive heart failure (CHF). Intravenous nitroglycerin was titrated to reduce the pulmonary artery wedge pressure by 30 to 50% and maintain this reduction for 4 hours. Afler 60 minutes of nitroglycerin administration, the mean decrement in wedge pressure was 10.0 f 1.7 (standard error) mm Hg (35%) and plasma ANF was 65.3 f 13.9 pmol/liter (35%). The initial decrease, sustained reduction and later increase in plasma ANF levels closely paralleled the changes in pulmonary arterial wedge (r = 0.94, p
METHODS Study population:

From the Department of Medicine, Auckland Hospital, Auckland, and the Department of Endocrinology, the Princess Margaret Hospital, Christchurch, New Zealand. This study was supported in part by grants from the National Heart Foundation and Medical Research Council of New Zealand. Manuscript received May 5, 1988; revised manuscript received September 26, 1988, and accepted September 30. Address for reprints: D.N. Sharpe, MD, Department of Medicine, Auckland Hospital, Park Road, Auckland, New Zealand.

Nine patients (8 men and 1 woman) with CHF were studied. Heart failure was due to ischemic heart disease in 6 and dilated cardiomyopathy in 3. One patient with dilated cardiomyopathy also had right-sided cardiac failure from bronchiectasis. Two patients were in New York Heart Association functional class II and 7 in class III. Age range was 46 to 76 years (mean 61.3). All patients were receiving furosemide (40 to 240 mg/day, mean 122), 5 were also receiving digoxin and none was taking vasodilators. No patient had severe renal impairment (serum creatinine 0.08 to 0.15 mmol/liter). Study protozoa: The study was approved by the Auckland Hospital Ethical Committee and all patients gave informed consent. Medications were withheld on the day of the study. Patients had a light breakfast at least 2 hours before catheterization and no subsequent food, tea or coffee during the study period. At 9 A.M., a 7Fr Swan-Ganz catheter was inserted in a brachial vein and advanced to the pulmonary artery. A 21 gauge cannula was inserted in a peripheral vein for subsequent nitroglycerin infusion. Throughout the day, patients remained semisupine in a quiet room but were supine for 5 minutes before each set of measurements.

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 15, 1989

ATRIAL

NATRIURET~C

FACTOR

TABLE I Clinical, Hemodynamic Pt 1 2 3 4

5 6 7 8 9

IN I~EAF~T FAILURE

and Hormone

Age (Y9, Sex

Diagnosis

60, 67, 56, 76, 68, 64, 61, 54, 46,

IHD IHD IHD IHD IHD IHD DC DC DC, CP

M M M M M

F M M M

*Average of 2 recordings. ANF = atrlal natriuretic factor; pressure.

CP = car pulmonale:

Data Before Nitroglycerin

Infusion*

Furosemide (w/day)

ANF (pmol/liter)

RA (mm Hg)

PAW (mm Hg)

240

170

160

135

60

113.5

9.5 7.5 10

33.5 27 24.5

160 120 40 120 80 120

DC = dilated

cardiomyopathy;

Two hours after catheter insertion, baseline hemodynamic and hormone measurementswere made and repeated after 1.5mintues. Intravenous nitroglycerin was then infused at a rate of 10 pg/min and increased in increments of 10 ,ug/min every 2 minutes to produce a reduction of 30 to 50% in pulmonary artery wedge pressure. The infusion rate was subsequently adjusted to maintain this reduction for the next 4 hours. Measurements were made 10, 20 and 30 minutes and 1, 2, 3 and 4 hours after the start of the infusion. The infusion was then stopped and further measurementsmade after 10, 30 and 60 minutes. Hemodynamic measurements: Heart rate, blood pressure, right atria1 pressure, pulmonary artery pressure and pulmonary artery wedge pressurewere recorded. Heart rate was taken from a continuous electrocardiogram and blood pressure measured by a sphygmomanometer. Mean arterial pressure was estimated as diastolic pressure plus one third of the difference between systolic and diastolic pressures. Hormone measurements: With each set of hemodynamic recordings, a blood sample was taken from the pulmonary artery onto ice for hormone assay. Plasma was separated at 4°C within 5 minutes and stored at -80°C. All samples were assayed as a single batch.

IHD = ischemic

114

12.5

31.5

332.5

10.5

399 176.5 174.5 121.5

11 6

31 23 29 27

15.5

15.5

11.5

heart disease: PAW = pulmonary

artery wedge pressure;

RA = right atrial

Plasma ANF was measuredby radioimmunoassayafter Vycor extraction using specific rabbit antisera.12Mean percentage recovery of ANF from plasma using Vycor was 95% at 40 pmol/liter. Using this assay, results showed excellent agreement (r = 0.96) with our previously published procedure.8Plasma sampleswere also assayedfor plasma renin activity,i3 aldosterone,14 cortisol (enzyme-linked immunosorbent assay)and catecholamines.15The coefficient of variation within assays ranged from 7.3% (ANF) to 14% (norepinephrine). Skitistical analysis: Results are expressedas mean f standard error. Variables were compared at each time point using a Pearsonproduct-moment correlation. The change in a value at each time point was obtained by subtracting an averageof 2 recordings made before nitroglycerin administration. Analysis of variance was used to determine whether this change was significant with time. RESULTS

Baseline characteristics are listed in Table I. All patients had a markedly increased wedge pressure and lesser increase of right atria1 pressure,apart from patient 9 who had biventricular failure. Initial ANF levels were also increased, but there was considerablevaria-

. .

.

I

.

.

. .

PRESSURE (mmH9)

218

-

0

RA

.

WEDGE

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

FIGURE 1. Plasma ANY versus right atrial (RA) and pulmonary artery wedge pressure. Valuqs are the mean of 2 measurements before nitroglycerin administration.

tion among patients and a poor correlation with both wedge(r = 0.05, p = 0.90) and right atria1 pressures(r = 0.00, p = 1.0) (Figure 1). With nitroglycerin, a satisfactory reduction in wedge pressurewas achievedin all patients within 30 minutes; the doserequired ranged from 50 to 245 ,ug/min. This was associatedwith a similar rapid decreasein plasma ANF. The reduction in wedge and right atria1 pressures was maintained for the next 3.5 hours. Over that time, plasma ANF remained at the reduced level (Figure 2). After 60 minutes, the mean reduction in wedge pressure was 10.0 f 1.7 mm Hg (35%), right atria1 pressure 3.8 f 0.75 mm Hg (38%) and ANF 65.3 f 13.9 pmol/liter (35%). One patient experienced a transient vasovagal episode that responded rapidly to atropine and a reNITROGLYCERIN

I/tI’iI

ANF

(pmol/l)

i

I

I

duced nitroglycerin infusion rate. After the infusion, plasma ANF levels increased together with the wedge and right atria1 pressures. At each time point, mean ANF levels correlated closely with mean wedge (r = 0.94, p
WEDGE

WEDGE -8

10i 12 1 FIA

Crnmlg)

8I

Plasma ANF, ~u~rnona~ artery wedge and right pressures plotted before, during and after nitroglycerin infusion. Results are mean rt standard error in 9 patients. The changes in pressure and plasma ANF from 30 pared with initial values are all h@dy minutes to 4 hou

IGURE 3. Percent change from sus percent change in pulmonary individual values obtained during infusion are plotted together with group means at each time point.

baseline in plasma ANF verartery wedge pressure. The and after the nitroglycerin the best fit line through the

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 15, 1989

ATRIAI.

NATRIURETIC

FACTOR

IN HEART

FAILURE

the end of the infusion and decreasedto 142 f 42 pg/ ml (p = 0.16) 60 minutes after the infusion. DISCUSSION This study of patients with chronic CHF showsthat an acute and sustained decreasein left and right atria1 pressuresis associatedwith a similar pattern of change in ANF secretion. A number of studies have compared a single hemodynamic and ANF measurement during cardiac catheterization, with most7yg-11(but not a1116) finding a good correlation. In addition, there are other anecdotal reports on the effect of treatment.17J8A recent study in patients with CHF showed a reduction in plasma ANF levels after sublingual nitroglycerin,lg but the ANF responseto acute and sustained atria1 pressure reduction has not been previously studied. In man, it is not yet known whether the right or left atrium is the major site of ANF release.Animal studies using partial occlusion of the atrioventricular valves*Oor of the aorta and pulmonary arteries*’ suggestthat both are important. Goetz et al*Ofound an increasein plasma ANF of 11.0 and 10.2 pmol/liter for each l-mm Hg NITROGLYCERIN

800

NOREPINEPHRINE (pa/ml)

700 !

3

PLASMA

I

RENIN 2

ACTIVITY (nmol/l/h)

I

!

600 1 ALDOSTERONE (pmol/l)

‘O” 300*oo-

i\! 1 u,$ ‘\ ;i-pkiTT*T i-q i i

CORTISOL

600

(nmol/l) 400

0

1

2

TIME

3

4

5

(hours)

FIGURE 4. Plasma norepinephrine, renin activity, aldosterone and corlisol plotted before, during and after the nitroglycerin infusion. Results are mean & standard error in 9 patients. The asferisks indicate all significant changes from Initial values (* p
220

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

increase in right and left atria1 pressures,respectively. We observeda closer correlation betweenplasma ANF and wedge rather than right atria1 pressure.However, our patients were initially included on the basis of a high wedge pressureand nitroglycerin was subsequently titrated against the wedge rather than the right atria1 pressure. Hence we cannot conclude that left atria1 pressure (stretch) is the more important determinant of ANF secretion in these patients. The average overall reduction in plasma ANF of 60 pmol/liter with nitroglycerin was associatedwith reductions in wedge and right atria1 pressuresof approximately 10 and 4 mm Hg, respectively. Consequently, each l-mm Hg reduction in right atria1 pressureis associated with approximately a 15pmol/liter reduction in plasma ANF. Raine et alli examined the effect of exercise on right atria1 pressureand plasma ANF in a small group of patients during a cardiac catheterization study. They also obtained a figure of 14 pmol/liter for the increment in plasma ANF with each l-mm Hg increment in right atria1 pressure. They found that the subgroup with an elevated right atria1 pressure at rest showeda lesser increment in plasma ANF with exercise than those with a normal pressure and concluded that the atrium may be depletedof ANF, as found in the cardiomyopathic BIO 14.6 hamster. However, in this animal model it is now appreciated that, although tissue stores are depleted, ANF secretion is stimulated and circulating plasma levels are in fact elevated.** Factors other than elevated atria1 pressure may contribute to elevation of plasma ANF. A diminished metabolic clearance rate is possiblebut unlikely in view of our previous findings of normal clearance in patients with heart failure.23 Animal studies suggestthat the sympathetic nervous systemmay influence ANF release with evidence for both an a~-*~and az-adrenergic2seffect. In normal man, a pressorinfusion of norepinephrine tended to increase plasma ANF levels more than an equipressor dose of angiotensin II.26 However, when an infusion of norepinephrine was combined with sodium nitroprusside to return blood pressureto control levels, plasma ANF also returned to normal despite a continuing markedly elevated norepinephrine level. Our study also suggeststhat the sympathetic nervoussystem does not play an important role in man, at least in the acute modulation of ANF release.Plasma epinephrine and norepinephrine tended to show changesreciprocal to those seen in plasma ANF. Perhaps alterations in atria1 wall compliance in heart failure affect the relation between atria1 pressure and ANF secretion. Although nitroglycerin induced abrupt and sustained reductions in atria1 pressure, there was no significant increase in heart rate related to increased plasma norepinephrine levels, possibly due to downregulation of adrenergic receptors.These findings are consistentwith previous reports of dysautonomia in CHF.27 Similarly, plasma renin activity responseswere negligible-yet there was a distinct and early adrenocortical responsepresumably representing an increase in adrenocorticotrophic hormone secretion in responseto a decreasein

arterial pressure.The reason for this difference in adrenocorticotrophic hormone and renin responsesto vasodilation is unclear but may relate to an inhibitory effect on renin secretion from overloaded cardiopulmonary mechanoreceptorsin patients with CHFJ8 It is interesting to note that ANF infusions in patients with heart failure induced comparable decreasesin atria1 pressure to those observed in the present study but failed to evoke an adrenocortical response until the ANF infusionswere terminated.23Taken together, these observations support an inhibitory effect of ANF on aldosterone secretion29and raise the possibility that part of the aldosteroneincreasewe observedresulted from the rapid decline in plasma ANF. In this context it is also relevant to comment on the recent finding of increased ANF levels for a given atria1 pressure with long-term captopril therapy and failure of ANF to decreasewith changeto a standing position despite a reduction in atrial pressures.30 This suggeststhat changesin atria1 compliance of threshold for ANF release may occur with long-term captopril therapy. Acknowledgment: We are grateful to Robyn Cliffe and Claire Allison for expert secretarial assistanceand Heather Smith for the artwork.

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THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 15, 1989