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(Circulation. 1996;93:2037-2042.)
© 1996 American Heart Association, Inc.

Articles

Effects of Brain Natriuretic Peptide on Exercise Hemodynamics and Neurohormones in Isolated Diastolic Heart Failure

Peter B.M. Clarkson, MB, ChB, MRCP; Nigel M. Wheeldon, MD, MRCP; Robert J. MacFadyen, BSc, MD, PhD, MRCP; Stuart D. Pringle, MD, FRCP; Thomas M. MacDonald, MD, FRCP

From the University Departments of Clinical Pharmacology (P.B.M.C., R.J.M., T.M.M.) and Cardiology (S.D.P.), Ninewells Hospital and Medical School, Dundee, United Kingdom, and the Cardiothoracic Unit, Northern General Hospital (N.M.W.), Sheffield, United Kingdom.

Correspondence to Peter B.M. Clarkson, University Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, DD1 9SY United Kingdom.

	Abstract

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Background Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure.

Methods and Results Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23±2 mm Hg; BNP, 16±2 mm Hg; P<.01) and mean pulmonary artery pressure (placebo, 34±3 mm Hg; BNP, 29±3 mm Hg; P<.05) during exercise without affecting changes in heart rate, systemic blood pressure, or stroke volume. In response to BNP, there was significant suppression of plasma aldosterone concentration (placebo, 551±107 pmol/L; BNP, 381±56 pmol/L; P<.05).

Conclusions BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.

Key Words: peptides • heart failure • hemodynamics

	Introduction

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In recent years, it has become increasingly recognized that impaired left ventricular diastolic function can significantly affect overall cardiac performance and contribute to the signs and symptoms experienced by patients with heart disease.^{1 2} Of all patients with symptoms and signs suggestive of heart failure, only 60% have reduced systolic contractility, whereas almost all have evidence of impaired diastolic function.^{3 4 5 6} The syndrome of diastolic heart failure is difficult to distinguish from systolic heart failure on the basis of signs and symptoms^{5 7} and thus is often unrecognized.^{6 8 9 10} This condition has diagnostic, prognostic, and therapeutic implications distinct from those of systolic heart failure.^{10 11 12 13 14 15} The symptoms associated with systolic and diastolic heart failure are similar, ie, dyspnea on exertion and easy fatigability.^{3 16} The hallmarks of this syndrome are normal left ventricular systolic performance and demonstration of elevated left ventricular filling pressures either at rest or on exercise.^{6 17} In patients with severe diastolic heart failure, a failure of the Frank-Starling mechanism has been demonstrated.¹⁷

BNP initially was isolated from porcine brain in 1988,¹⁸ but despite its name, it is produced predominantly by the ventricular myocyte.^{19 20} BNP has considerable structural similarity to ANP and is thought to mediate its biological actions via the same guanylate cyclase–linked receptors,²¹ which are present in the adrenal cortex,²² vascular smooth muscle cells,²³ renal glomeruli,²⁴ and heart.²⁴

BNP has well-recognized natriuretic, diuretic, hypotensive, and smooth muscle relaxant effects.^{18 21} In addition, recent studies both by our group²⁵ and by others²⁶ suggest that BNP has a direct effect (a positive lusitropic effect) on myocardial relaxation, one of the principal components of diastolic function.

The aim of the present study was to evaluate the effect of BNP on hemodynamics and neurohormonal responses, both at rest and during exercise, in patients with isolated diastolic heart failure.

	Methods

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Patient Population
This study was approved by the Tayside Committee on Medical Research Ethics. All patients had been referred for echocardiography or radionuclide ventriculography over a 2-year period to evaluate symptoms of chronic dyspnea. A thorough search of the echocardiography and radionuclide databases was performed to locate patients eligible for study. All patients were diagnosed as having isolated diastolic heart failure on the basis of the following criteria: New York Heart Association clinical grade II or III symptoms; normal routine hematological and biochemical parameters; no previous history of myocardial infarction, angina pectoris, or diabetes mellitus; in normal sinus rhythm; no Q waves on resting ECG; no ST segment changes suggestive of ischemia on exercise stress testing; normal left ventricular systolic function on either echocardiography or radionuclide ventriculography; no clinical or echocardiographic evidence of valvular disease or pericardial disease; and no spirometric or radiographic evidence of pulmonary disease. In total, seven patients were included in the study, each of whom provided written informed consent. One patient had normal left ventricular filling pressures at rest and during dynamic exercise during both placebo and BNP infusion and therefore was excluded from the analysis, since a diagnosis of isolated diastolic heart failure was excluded. Individual patient characteristics are described in Table 1. Each patient had familiarization trials with the supine multistage bicycle ergometer before the definitive study (Bosch ERG 5SSP, Dimeg Medzinelektronik).

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Protocol
Patients were studied in a balanced, randomized, single-blind, placebo-controlled, crossover study. All cardiovascular drug therapy was withdrawn at least 1 week before the study. Diuretic treatment was withdrawn a minimum of 3 days before the study. One 18-gauge intravenous cannula was inserted into a forearm vein for infusion of either BNP or placebo. After administration of local anesthetic (1% lidocaine), a 7F vascular sheath was inserted into a subclavian vein. Through this sheath, a triple-lumen, thermistor-tipped pulmonary flotation catheter (Edwards Swan Ganz, 131H-7F Baxter) was positioned in the pulmonary artery. After 1 hour of supine rest, baseline hemodynamic measurements were taken and blood samples (30 mL) were taken from the subclavian vein for determination of ANP, BNP, angiotensin II, and aldosterone levels.

After baseline measurements, a continuous infusion of either placebo (0.9% [wt/vol] saline) or human BNP (Clinalfa, at a dose of 5 pmol·kg^-1·min^-1 in a similar volume of 0.9% saline) was begun. The infusion rate of 5 pmol·kg^-1·min^-1 was chosen because this rate has been shown both to influence diastolic filling in normal subjects and to represent a pathophysiological plasma concentration.²⁵ Hemodynamic measurements and blood sampling were repeated after 30 minutes of infusion.

Exercise testing was then performed with patients in the supine position on a bicycle ergometer as described elsewhere.²⁷ The workload was begun at 25 W and increased by 25 W in 3-minute stages until exhaustion. Hemodynamic measurements were taken at the end of each 3-minute stage and at maximal exercise. Another blood sample was taken at maximal exercise.

Patients were permitted a light meal (with no more than 200 mL fluid) during the rest period. After 3 hours' rest, the protocol was repeated with the appropriate alternative treatment.

Hemodynamic Measurements
Values of systemic arterial blood pressure were measured in triplicate by use of a semiautomatic sphygmomanometer (Dinamap Vital Signs Monitor 1846, Critikon) at baseline, after 30 minutes of infusion, at the end of each exercise stage, and at maximal exercise.

Both MPAP and mean PCWP were recorded by use of the pulmonary artery flotation catheter at baseline, after 30 minutes of infusion, at the end of each 3-minute exercise stage, and at maximal exercise. Pressures were recorded by a Hewlett Packard pressure transducer from a zero reference at midchest level. Cardiac output was calculated in triplicate at baseline, after 30 minutes of infusion, and on maximal exercise by use of the thermodilution technique with 10-mL bolus injections of ice-cold saline (Hewlett Packard 545 cardiac output computer). The thermodilution curve was checked for consistency before the results were accepted as reflecting cardiac output. Irregular curves (not smooth and not characterized by a rapid peak), especially during exercise, were excluded from the study. Cardiac index, stroke volume index, and systemic vascular resistance index were calculated by use of standard formulas.

Neurohormonal Collection and Analysis
Blood samples were divided into aliquots for analysis of plasma ANP, BNP, angiotensin II, and aldosterone. Aliquots were taken into chilled tubes that contained EDTA (potassium salt) and 4000 kallikrein inhibitory units of aprotinin (Trasylol; Bayer) as preservative for the measurement of ANP and BNP. Samples for angiotensin II assay were taken into chilled glass tubes that contained a solution of 0.05 mol/L o-phenanthroline, 2 g/L neomycin, 0.125 mol/L EDTA (disodium salt), and 2% ethanol. The final aliquot was taken into chilled lithium heparin tubes for measurement of aldosterone. All samples were placed on ice, centrifuged at 4°C, and then separated and stored at -70°C (ANP, BNP, and angiotensin II) or -20°C (aldosterone) until assayed. Plasma ANP, BNP, angiotensin II, and aldosterone were measured after extraction by use of commercially available radioimmunoassay kits (ANP and BNP, Peninsula Laboratories Europe; angiotensin II, Sorin Biomedica; and aldosterone, Nichols Institute Diagnostics BF). The normal ranges in our laboratory are as follows: ANP, 2.4 to 10.5 pmol/L; BNP, 2.3 to 4.5 pmol/L; angiotensin II, <108 pg/mL; and aldosterone, 21 to 415 pmol/L. The interassay coefficients of variation for hormonal assays are as follows: ANP, 12.6%; BNP, 9.9%; angiotensin II, 11.6%; and aldosterone, 4.5%.

Statistical Analysis
All data were analyzed by use of the Statgraphics software package (STSC Software Publishing Group). ANOVA (repeated at each dose increment, with subject and treatment used as within factors) and Bonferroni multiple-range tests were performed to determine the significance of BNP-induced changes in hemodynamic and neurohormonal indexes, with a value of P<.05 taken to indicate significance. Results are presented in the tables as mean differences compared with placebo and the associated 95% CIs and in the figures as mean changes from baseline.

	Results

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Tolerance
All patients completed the study. There were no complications after central venous cannulation. Both exercise and BNP infusion were well tolerated in all patients except one who felt light-headed on standing after completion of the study and removal of all catheters. A 20-mm Hg postural fall in systolic blood pressure was present. Symptoms resolved spontaneously within 30 minutes, and no specific action was required.

Baseline Measurements
Baseline measurements of both hemodynamic and neurohormonal parameters were similar in both the BNP and placebo limbs of the study (Table 2).

View this table: [in this window] [in a new window]   Table 2. Comparison of Baseline Parameters

Exercise Time
Exercise duration was unaffected by BNP infusion (placebo, 8.5±0.7 minutes; BNP, 8.7±0.5 minutes; P=.76).

Hemodynamics
Exercise during placebo infusion was associated with the expected increases in heart rate, blood pressure, PCWP, and cardiac index. A small, nonsignificant increase in stroke volume index was also observed. During BNP infusion, no change in resting hemodynamics was seen. During exercise, there was a marked attenuation of both the increase in PCWP and MPAP with exercise (Figs 1 and 2). The rise in systemic arterial blood pressure and the increase in heart rate with exercise were unaffected by BNP infusion. There were no changes in cardiac index, stroke volume index, or other calculated parameters (Table 3).

View larger version (11K): [in this window] [in a new window]   Figure 1. Changes in MPAP with BNP infusion compared with placebo. Results are expressed as mean±SEM. Time points: -30 minutes corresponds to baseline; 0, resting measurements after 30 minutes of infusion; and every third minute, an exercise increment of 25 W. *P<.05.

View larger version (11K): [in this window] [in a new window]   Figure 2. Changes in PCWP compared with placebo. Results are mean±SEM. *P<.05, **P<.01.

View this table: [in this window] [in a new window]   Table 3. Hemodynamic Parameters

Neurohormones
Plasma concentrations of both ANP and BNP at baseline were elevated outside the normal range, whereas angiotensin II and aldosterone concentrations were within normal limits (Table 4). During exercise, an increase in both ANP and BNP concentration was observed, together with small, nonsignificant increases in angiotensin II and aldosterone.

View this table: [in this window] [in a new window]   Table 4. Effects of BNP Infusion on Plasma Neurohormones at Rest and on Maximal Exercise

BNP infusion caused an increase in circulating plasma BNP concentration and significantly suppressed aldosterone both at rest and on exercise. Both plasma ANP concentration and plasma angiotensin II remained unaffected by BNP infusion.

	Discussion

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This small, placebo-controlled study is the first to demonstrate the central cardiac hemodynamic effects of BNP on the exercise response in patients with diastolic heart failure. Patient selection for this study was characterized by rigid criteria to exclude alternative causes of dyspnea and/or exercise limitation. The predominant characteristic of our patient group was long-standing arterial hypertension and concentric LVH, which is in keeping with the findings of several previous studies of patients with diastolic heart failure.^{3 4 14} Results were similar in patients with and without LVH.

LVH is well recognized to affect left ventricular diastolic as well as systolic performance.^{28 29} Sobue and coworkers³⁰ demonstrated that LVH is associated with an exaggerated rise in PCWP during supine exercise. However, patients with hypertension but without LVH also may have clinically significant alterations in indexes of diastolic function.^{6 31} Coronary flow reserve is reduced in patients with LVH.³² A decreased vascular density has been observed in the pressure-overloaded left ventricle, particularly in the subendocardium,³³ together with medial hypertrophy in coronary resistance vessels.³⁴ Therefore, there is a transmural gradient of coronary blood flow in LVH associated with reduced subendocardial blood flow that is accentuated by exercise.³⁵ LVH therefore predisposes to subendocardial ischemia on exercise with resultant impairment in diastolic function. Additionally, hypertrophied myocardium displays a prolonged calcium transient.³⁶ This is reflected by a prolongation of myocardial relaxation that can be aggravated further by myocardial ischemia.³⁷ Factors such as excess collagen infiltration of myocardium can also affect the left ventricular diastolic pressure-volume relation.^{38 39 40}

Hemodynamics
In the present study, the rise in PCWP on exercise was similar to that reported by Kitzman and colleagues¹⁷ in a group of patients with isolated diastolic heart failure. In that study, a group of seven patients with severe diastolic heart failure, the majority of whom demonstrated clinical and radiographic pulmonary edema at rest, was described. In those patients, a marked rise in PCWP but no rise in stroke volume on exercise was described. It is probable that the patients described in the present study had less severe heart failure, since symptoms were present only on exertion. This may explain why a small increase in stroke volume was observed in our study.

Infusion of the dose of BNP used in the present study caused no significant changes in resting blood pressure, heart rate, or cardiac hemodynamics. On exercise, however, a marked reduction in the rise in PCWP was consistently observed compared with placebo infusion. There were no changes in the stroke volume index, cardiac output, blood pressure, or heart rate compared with placebo. Similarly, no changes in either heart rate or blood pressure were seen. As PCWP reflects left ventricular end-diastolic pressure even during exercise,⁴¹ these results suggest that BNP exerts beneficial effects on left ventricular function during exercise in patients with isolated diastolic heart failure. In systolic heart failure, BNP reduces PCWP and increases stroke volume.⁴² As patients with systolic heart failure almost invariably have abnormalities in diastolic function,^{3 4 5 6} BNP may mediate these changes in part through alteration of the diastolic properties of the left ventricle.

BNP is known to reduce intravascular volume⁴³ and to influence left ventricular diastolic properties.^{26 27} It is likely that the reduction in PCWP seen in the present study reflects a combination of these factors, since reduction of preload alone would be expected to reduce stroke volume unless the diastolic pressure-volume relationship of the left ventricle was favorably altered.

Patients in the present study were affected by chronic fatigue or breathlessness on exertion. In chronic systolic heart failure, symptoms and exercise capacity are poorly related to central cardiac hemodynamics. Symptomatic limitation of exercise may be mediated by a wide variety of stimuli that originate centrally from the cardiopulmonary bed or from peripheral hypoperfusion/structural alterations, eg, in skeletal muscle.^{44 45 46 47 48} In the present short-term study based on a small number of subjects, therefore, there was no effect on exercise time despite a favorable attenuation of the pulmonary hemodynamic response to exercise.

Neurohormones
The present study demonstrates that plasma concentrations of both ANP and BNP in the resting state are elevated outside the normal range and increase further during supine bicycle exercise in patients with diastolic heart failure. Elevation of ANP concentrations during exercise has been noted previously in normal subjects,⁴⁹ patients with angina pectoris,⁴⁹ and patients with systolic heart failure.⁵⁰ BNP, however, rises during exercise only in disease states.^{49 50} Resting concentrations of angiotensin II and aldosterone were within the normal range at baseline and did not change significantly during exercise.

During infusion of BNP, plasma BNP concentrations rose as expected to 15 times baseline levels. There was a significant reduction in aldosterone both at rest and at maximal exercise in response to the infusion of BNP. ANP and angiotensin II concentrations were unaffected by BNP infusion.

The reduction in plasma aldosterone during BNP infusion relates to a direct effect on secretion⁵¹ and has been observed previously in normal subjects⁴² and in patients with systolic heart failure.⁴² BNP does not influence plasma renin activity in normal subjects^{42 52} or in patients with systolic heart failure⁴² ; therefore, the lack of suppression of angiotensin II in diastolic heart failure is in keeping with previous findings. The failure of BNP to reduce ANP concentrations appears paradoxical at first because BNP infusion reduces PCWP, which is expected to lead to decreased ANP secretion.^{22 53} However, Yoshimura and colleagues⁴² actually observed an increase in ANP concentration despite a reduction in both PCWP and right atrial pressure during BNP infusion in both normal subjects and those with congestive heart failure. This apparent paradox can be explained by the large amounts of exogenous BNP that compete with endogenous ANP for a limited number of clearance mechanisms, which results in increased amounts of ANP not being cleared.⁴²

Study Limitations
We appreciate that our report is based on a small number of patients studied. However, we believe that these patients represent a well-defined study population of patients with diastolic heart failure who were extracted from a much larger group of patients with possible diastolic heart failure. Further limitations to recruitment were imposed by the necessity to provide detailed information on the potential complications of central catheterization before study. In addition, although we are well aware of the problems of short-term hemodynamic measurements, patients were studied on a single day to avoid multiple catheter insertions. Reassuringly, baseline measurements were similar before either BNP or placebo infusion, and no carryover effects were seen. It would be unlikely, given the known clearance of BNP,⁴³ that the relatively short interval between studies significantly affected the results.

Summary
In conclusion, in patients with diastolic heart failure, BNP infusion exerts beneficial effects on cardiac performance during exercise, which results in a reduction in PCWP without alteration in stroke volume. Additionally, BNP infusion in patients with isolated diastolic heart failure suppresses aldosterone both at rest and on exercise. These results indicate that increased secretion of BNP may play an important compensatory role in diastolic heart failure and suggest possible therapeutic approaches to this condition with either neutral endopeptidase inhibitors or, perhaps in the future, natriuretic peptide receptor agonists.

	Selected Abbreviations and Acronyms

 

ANP = atrial natriuretic peptide BNP = brain natriuretic peptide LVH = left ventricular hypertrophy MPAP = mean pulmonary arterial pressure PCWP = pulmonary capillary wedge pressure

	Acknowledgments

 
We acknowledge the financial support of both Tenovus Scotland and the Anonymous Trust of Dundee for help in the purchase of equipment used in this study, and we thank J. Thomson, W. Coutie, and C. MacLeod for their assistance in this project.

Received October 30, 1995; revision received January 17, 1996; accepted January 22, 1996.

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