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European Journal of Heart Failure 1999 1(4):371-377; doi:10.1016/S1388-9842(99)00058-6
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© 1999 European Society of Cardiology

Disruption of the relationship between renin and atrial natriuretic peptide early in the course of ventricular dysfunction

David P. Dutkaa,*, Sundeep Puria, Rachel Stronga and John G.F. Clelandb

a Imperial College of Science, Technology and Medicine, National Heart and Lung Institute (Hammersmith Campus) Du Cane Road, London W12 0NN, UK
b Foundation Chair in Cardiology, University of Hull, Castle Hill Hospital Castle Road, Cottingham, Hull HU16 5JQ, UK

* Corresponding author. Tel.: +44-181-383-3748; fax: +44-181-383-3742. E-mail address: d.dutka{at}ic.ac.uk (D. P. Dutka)


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Plasma renin activity is normal in left ventricular dysfunction in the absence of diuretic therapy. In health there is a reciprocal relationship between renin and atrial natriuretic peptide (ANP) but a positive correlation in advanced heart failure. The relationship between renin and ANP in mild left ventricular dysfunction is unknown.

Methods and Results: Patients with left ventricular dysfunction (n = 35, 18 without diuretic therapy) were compared to 20 age-matched healthy subjects. Plasma concentrations of active renin (PARC), ANP and norepinephrine were measured after 20 min rest and 45 min after an infusion of normal saline (10 ml/kg body wt.). Basal plasma ANP was increased in patients with left ventricular dysfunction compared to healthy subjects, whether or not they were receiving diuretics. PARC was similar in healthy controls and patients untreated with diuretics but was increased in diuretic treated patients. After saline loading in healthy subjects PARC fell while ANP rose. Patients with left ventricular dysfunction had a smaller decline in PARC, that did not achieve statistical significance, but had a greater increase in plasma ANP compared to healthy subjects (P < 0.05). The close reciprocal relationship between PARC and ANP observed in healthy subjects before and after saline loading (r = 0.8, P < 0.001 and r = 0.6, P < 0.01) was weakened in those not receiving diuretics (r = 0.4, P < 0.05 and r = 0.24, ns) and lost in those receiving diuretics (r = 0.1 and r = 0.08).

Conclusions: Patients with left ventricular dysfunction have a disturbance of the normal reciprocal relationship between PARC and ANP which antedates diuretic treatment. This should be taken into account when interpreting plasma neuroendocrine measurements in patients with ventricular dysfunction.

Key Words: Heart failure • Renin • ANP • Neuroendocrine activation

Received June 8, 1999; Revised September 10, 1999; Accepted September 20, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In healthy subjects there is an inverse relationship between activation of the renin–angiotensin system and plasma natriuretic peptide which may be determined largely by changes in sodium balance [1]. The activity of the renin–angiotensin system declines in normal subjects in response to a saline load, effects mediated through renal macula densa and atrial reflexes [2], resulting in a fall in vascular tone that attenuates any increase in arterial pressure [3]. Increases in atrial wall tension stimulate secretion of natriuretic peptides that will enhance sodium excretion, restoring sodium balance towards normal [4,5].

Plasma concentrations of atrial natriuretic peptide are increased in patients with asymptomatic cardiac dysfunction and predict the onset of heart failure in elderly subjects and following myocardial infarction [6,7]. The natural history of the renin–angiotensin system activation is less clear. Activation occurs early after myocardial infarction in the presence of left ventricular dysfunction and persists for at least 12 days even in the absence of diuretic therapy [6]. In patients with chronic asymptomatic left ventricular dysfunction normal levels of plasma renin–angiotensin hormones have been reported [8,9] with activation only following the introduction of diuretics.

Volpe et al. [10] suggested that although plasma concentrations of ANP measured under basal conditions are elevated in untreated left ventricular dysfunction, plasma concentrations do not increase further after saline loading although plasma renin activity declined normally [3,10]. Blunted increases in atrial natriuretic peptide in response to salt and water loading may be responsible, in part, for the tendency to salt and water retention in heart failure [3,10]. However, failure of ANP to increase in response to sodium intake would also have important repercussions for the use of this peptide for clinical monitoring of ventricular dysfunction and heart failure.

To gain an insight into the hormonal mechanisms which follow volume expansion with saline in patients with cardiac impairment, we studied the neuroendocrine responses to a saline load in patients with ventricular dysfunction due to ischaemic heart disease and healthy control subjects.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
The study was approved by the Hospital Ethical Committee and fully informed consent was obtained from the patients who participated in the study.

Thirty five patients with left ventricular dysfunction and 20 age-matched healthy control subjects were studied. The patients were selected on the basis of a reduced echocardiographic ejection fraction (<40%) at the time of assessment for ACE inhibitor therapy. All patients were in sinus rhythm and none had hypertension, renal impairment or any intercurrent illness. All patients had had a prior, remote myocardial infarction; patients with a myocardial infarction within the previous 3 months were excluded. The patients fell into two groups on the basis of diuretic treatment; 18 were asymptomatic and were receiving no treatment other than low dose aspirin and 17 were receiving frusemide [daily dose of 28 ± 4 mg (mean ±S.D.), maximum dose 40 mg/day] in addition to aspirin. The control subjects were identified from among hospital staff, friends or relatives of patients. Subjects with a history of possible cardiac symptoms, other illnesses, an abnormal physical examination or electrocardiogram or abnormal haematology or routine biochemistry were excluded.

Patients and controls were evaluated by a dietician and placed on a 100 mmol/day sodium and 40 mmol/day potassium diet for 3 days prior to study to reduce the influence of diet on neurohormones. Patients and controls were asked to abstain from all alcohol for at least 24 h prior to study and to generally avoid excessive alcohol intake. Caffeine containing beverages were prohibited on the day of the study.

Patients and control subjects were placed in the semi-recumbent position and a cannula inserted into a fore-arm vein 20 min prior to drawing a 20-ml sample of venous blood into chilled tubes, centrifuged immediately at 4°C and stored at –70°C until assay. The plasma concentration of active renin and atrial natriuretic peptide (irANP) were measured by radio-immunoassay and plasma norepinephrine by high performance liquid chromatography [11].

The patients and control subjects then received a saline load (0.9% saline, 10 ml/kg) over 30 min and further samples for neuro-hormones taken 15 min following the end of the infusion.

2.1. Statistical methods
The results were analysed using analysis of variance with Bonferroni correction for testing within the three groups and the Mann–Whitney test used to compare the groups. The results are presented as mean, median and range unless otherwise indicated.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The mean age of the patients was 58±4 (S.D.) years and the control subjects 58±7 years. The mean left ventricular ejection fraction was 36±1% (Table 1). No significant differences were noted between groups in terms of anthropological measurements, blood pressure or routine biochemistry. All the patients completed the study and none developed symptoms or signs of overt heart failure following the saline load.


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  		Table 1 Demographic and functional data in the control subjects and patients with asymptomatic and diuretic-treated left ventricular dysfunctiona

 
3.1. Saline loading studies
3.1.1. Resting pre-saline
The mean resting plasma concentration of atrial natriuretic peptide was significantly higher in the patients with left ventricular dysfunction not receiving diuretic therapy compared to the age-matched control group (Fig. 1), but plasma concentrations of active renin and norepinephrine were not significantly different after correction for multiple comparisons (Table 2). Patients with left ventricular dysfunction receiving diuretics had increased plasma concentrations of atrial natriuretic peptide, active renin and norepinephrine compared to controls. Although trends were noted, no statistically significant differences in plasma concentrations between patients with and without diuretic treatment were observed.


Figure 1
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  		Fig. 1 Plasma active renin concentration (a, PARC, U/ml) and atrial natriuretic peptide (b, ANP) before (B) and after saline (S) loading (10 ml/kg) in control subjects, patients with asymptomatic left ventricular dysfunction (ALVD) and patients with left ventricular dysfunction receiving diuretic therapy (LVD). The median for each group is represented by the horizontal line.

 


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  		Table 2 Plasma hormones levels (mean, median and range) at rest in control subjects, patients with asymptomatic and diuretic-treated left ventricular dysfunction

 
3.1.2. Effect of saline loading
Plasma concentrations of ANP increased while PARC declined after saline loading in healthy volunteers (Fig. 1) but plasma concentrations of norepinephrine did not change. In patients with ventricular dysfunction the plasma concentration of ANP increased significantly. The mean increase in ANP concentration in the control subjects was 29.5±9.9 pg/ml, in the patient group without diuretics 53.2±33.1 pg/ml (P<0.05 compared to control) and in the diuretic treated patient group 34.7±42.5 pg/ml (not significantly different from the control). Both PARC and norepinephrine did not decline significantly after saline loading in patients with LVD.

3.1.3. Inter-relationships between ANP, PARC and norepinephrine
The strong inverse relationship between plasma concentrations of ANP and PARC in healthy subjects (r=0.8, P<0.001) was maintained after saline loading (Fig. 2a) but in patients with asymptomatic ventricular dysfunction the relationship was lost irrespective of whether the patients were receiving diuretic therapy or not (Fig. 2b,c). The fall in plasma active renin concentration after saline loading is related to the basal plasma level in health (r=0.92, P<0.0001, Fig. 3a) and this relationship, although weaker, is maintained in patients with ventricular dysfunction even in the presence of diuretics (r=0.79, P<0.001 and r=0.64, P<0.004 respectively, Fig. 3b,c). The change in plasma ANP concentration after saline loading was more varied and did not relate to the baseline level in either the control subjects (r=0.03, P=0.9, Fig. 3d) or the patients with symptomatic (r=0.5, P=0.08, Fig. 3e) or diuretic treated (r=0.1, P=0.7, Fig. 3f) ventricular dysfunction. No relationship was demonstrated between the plasma concentrations of norepinephrine and PARC, and norepinephrine and ANP.


Figure 2
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  		Fig. 2 Effect of saline loading (10 ml/kg) on plasma atrial natriuretic peptide and active renin concentration (PARC) in control subjects (a) demonstrating a decline in plasma renin concentration and rise in natriuretic peptide. Patients with asymptomatic ventricular dysfunction have a variable response (b) which is even more marked in those treated with diuretics (c).

 


Figure 3
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  		Fig. 3 Change in plasma active renin concentration (a–c) and atrial natriuretic peptide (d–f) after saline loading (10 ml/kg) as a function of the basal plasma level of the hormone in control subjects (a,d), patients with asymptomatic ventricular dysfunction (b,e) and patients receiving diuretics (c,f).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In health there is a dynamic reciprocal relationship between plasma renin and ANP reflecting the opposite effects of sodium intake on these hormones [12–14]. A high salt intake increases ANP and reduces renin [14]. This study shows that this relationship is markedly weakened in patients with ventricular dysfunction, even before the introduction of diuretics. It is possible that patients with ventricular dysfunction undergo a period of sodium retention regaining sodium balance but at a higher body sodium content [12]. Salt and water retention may be an important stimulus to increases in natriuretic peptides in these patients [13]. If asymptomatic ventricular dysfunction is considered a sub-clinical fluid retentive state how then should plasma renin be interpreted? A normal plasma renin in this setting could be judged inappropriately high.

The control of renin secretion in patients with left ventricular dysfunction is complex. A relative decline in arterial pressure with carotid and renal baroreflex activation via the sympathetic nervous system may be the major initial stimulus to renin secretion in this setting, possibly reinforced by renal vasoconstriction and a reduced sodium load delivered to the distal convoluted tubule. On the other hand a number of reflexes are also activated that limit the increase in renin. An increase in atrial pressure, due to ventricular dysfunction and fluid retention, reduces renin secretion through vagal reflexes and the rise in natriuretic peptides further inhibits renin release [15]. It would appear that those factors that should suppress renin in heart failure are limited in their effect and that renin is inappropriately high for any given level of ANP. The switch from the normal inverse relationship between ANP and renin observed in health to the direct correlation observed in advanced heart failure appears to start early in the natural history of ventricular dysfunction [5,16].

We observed no change in plasma norepinephrine with saline loading in this study, in contrast to the effect of increasing dietary sodium intake in patients with heart failure [17] and hypertension [18] which induces a decline in plasma norepinephrine. The decline of plasma norepinephrine in response to salt loading may occur slowly. Interestingly, administration of diuretics to patients with untreated heart failure, to increase sodium output, causes plasma norepinephrine to decline [19], whereas further doses of diuretic in patients with heart failure already on chronic diuretic therapy increases plasma norepinephrine [20]. The relationship between sodium balance and sympathetic activation in heart failure merits further investigation.

Volpe et al. studied patients with untreated ventricular dysfunction due to dilated cardiomyopathy or ischaemic heart disease before and after an acute saline load [10] and after a 6-day (250 mmol/day) sodium diet [3]. The authors suggested that the normal increase in atrial natriuretic peptdes in response to sodium loading was lost in patients with left ventricular dysfunction but that the magnitude of suppression in renin was similar to healthy controls. This is in contrast to the findings in this study where a larger infusion of saline was given over a shorter period of time. This may have produced a greater degree of atrial stretch and suggests that ANP, and possibly other natriuretic peptides, may have a limited role for therapeutic monitoring in chronic ventricular dysfunction and heart failure. Several reports have shown that ANP can track the response to therapeutic interventions that alter atrial pressure, such as diuretics [21] and nitrates [22]. The exception may be the therapeutic response to ACE inhibitors [23–25]. ACE inhibitors have been reported to reset the relationship between atrial pressure and plasma concentrations of ANP and therefore ANP may underestimate the fall in atrial pressure induced by ACE inhibitors [26,27].

One or more of the natriuretic peptides appear promising tools for the detection of LVD [11], the diagnosis of mild heart failure [28], and for prognostic purposes [29,30]. Healthy subjects had similar plasma concentrations of ANP after saline loading to patients with LVD on a controlled salt intake. Variations in salt intake could reduce the ability of plasma concentration of natriuretic peptides to distinguish between normal and abnormal cardiac function. The breakdown of the normal close reciprocal relationship between renin and ANP suggests a role for both hormones in the early diagnosis of ‘functional’ ventricular dysfunction.

Possible limitations of this study include the fact that only atrial natriuretic peptide was measured. The N–terminal-ANP response to acute saline loading would be difficult to interpret due to the relatively long half-life of this fragment of the peptide. Although brain natriuretic peptide (BNP) may offer a more robust measure of chronic ventricular dysfunction [11], it is not released in response to acute volume expansion in sufficient quantities to increase the plasma concentration [31], at least in normal volunteers. Whether this reflects the different sites of synthesis of ANP and BNP is unclear [31,32], but a failure of BNP to increase with salt loading could be advantageous for the diagnosis and monitoring of heart failure.

Although we observed no significant differences in the plasma concentrations of norepinephrine or renin between controls and patients with ventricular dysfunction who were not receiving a diuretic it is possible that a study with larger numbers might have. A sub-study of SOLVD demonstrated that patients with left ventricular dysfunction who were not receiving diuretic therapy and who were on an unrestricted sodium intake had elevated plasma concentrations of ANP and norepinephrine but not plasma renin activity [8,9]. Our study generally reinforces these findings although in there was only a trend for the plasma norepinephrine concentration to be elevated in those patients with ventricular dysfunction not receiving a diuretic. The greater neuro-endocrine activation in diuretic-treated patients, as also observed in the SOLVD data, may reflect the reasons for prescribing these agents rather than an effect of diuretics themselves.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
This study provides evidence that although resting plasma indices of the renin–angiotensin system activity may be normal, control of this hormonal system is perturbed even in patients with asymptomatic ventricular dysfunction.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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