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European Journal of Heart Failure 2002 4(1):63-72; doi:10.1016/S1388-9842(01)00197-0
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© 2002 European Society of Cardiology

Hemodynamic and plasma atrial natriuretic peptide responses to acute digitalis therapy in patients with normal and impaired left ventricular function

Wayne L. Miller*, Kent R. Bailey, Susan A. Weston, John C. Burnett, Jr. and Richard J. Rodeheffer

Division of Cardiovascular Diseases, Department of Biostatistics, Mayo Clinic and Mayo Foundation 200 First Street, SW, Rochester, MN 55905, USA

* Corresponding author. Mayo Clinic and Mayo Foundation, 200 First Street, SW, Rochester, MN 55905, USA. Tel.: +1-507-284-3685; fax: +1-507-284-4200. E-mail address: miller.wayne{at}mayo.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusions
 References
 
Background: Digitalis has a long history in the treatment of heart failure but its effects on cardiac hemodynamics and neurohormonal modulation are not well characterized.

Aims: The purpose of this study was to evaluate the relationship between atrial natriuretic peptide (ANP) and the hemodynamic responses to acute digitalis administration in patients with normal and impaired left ventricular function (LVD).

Methods and Results: Thirty patients were enrolled in the study, 20 with LVD (LVEF=22±8%) and 10 control subjects (LVEF=77±10%). Hemodynamics and plasma ANP concentrations were measured supine and with leg elevation before and after digitalis. In patients with normal ventricular function, the hemodynamic stress of leg elevation in the pre-digitalis state resulted in significant (P<0.05) increases in PAWP and MPAP. Digitalis administration in the supine position produced reductions in heart rate, PAWP, MPAP and CI; SVR was increased. In LVD patients leg elevation further increased PAWP, RAP and MPAP. Digitalis in the supine position, however, reduced RAP, MPAP and PAWP and increased CI. These improved hemodynamics were preserved during the stress of leg elevation. Leg elevation following digitalis resulted in increased ANP concentrations despite decreased cardiac filling pressures.

Conclusions: Acute digitalis administration results in hemodynamic improvement in LVD patients which may in part result from digitalis stimulated release of myocardial ANP under conditions of hemodynamic stress.

Key Words: Atrial natriuretic peptide • Heart failure • Digitalis • Hemodynamics

Received April 10, 2001; Revised June 26, 2001; Accepted September 7, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusions
 References
 
Digitalis glycosides have been used in the treatment of myocardial contractile dysfunction for more than 200 years. Despite this long history of therapeutic use, controversy persists regarding the appropriate role of digitalis in the treatment of patients with heart failure and normal sinus rhythm. In the Digitalis Investigation Group Trial of patients with symptomatic heart failure and sinus rhythm, digoxin therapy reduced the risk of hospitalization but did not provide a survival benefit [1]. Consensus on the role of digitalis is made still more uncertain by the development of converting enzyme inhibitor and beta-blocker therapies that have demonstrated survival benefits. Therefore, the rationale for digitalis therapy in the management of heart failure requires ongoing reassessment.

Atrial natriuretic peptide (ANP) has been demonstrated to be localized in secretory granules of the atria and to be released into the circulation as the result of atrial distension, volume expansion or tachycardia, i.e. stimuli that are associated with elevation of atrial pressures. Elevated plasma ANP concentrations are associated with asymptomatic and symptomatic left ventricular dysfunction and have been shown to have natriuretic, diuretic and vascular smooth muscle relaxing properties [2,3]. ANP exerts a salutory counter-regulatory effect, attenuating the deleterious vasoconstrictive and volume expansion effects that result from chronic activation of the sympathetic nervous and renin–angiotensin aldosterone systems.

Digitalis glycosides increase the influx of extracellular calcium as a mechanism of their positive inotropic action in myocytes. Calcium may also serve as a second messenger for pressure induced atrial release of ANP. Therefore, it has been hypothesized that digitalis may stimulate ANP release from the myocardium [4]. The response of ANP to digitalis administration is of particular interest since augmentation of ANP release could potentially contribute to the maintenance of a compensated state in patients with heart failure.

The purpose of this study was twofold. The first goal was to evaluate the relationship between ANP and the hemodynamic response to acute digitalis administration in patients with normal and impaired left ventricular function. Second, it was hypothesized that digitalis administration would result in an augmented ANP response to a provocative hemodynamic maneuver (leg elevation) that increases atrial pressure [5].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusions
 References
 
2.1. Study patients
The patients enrolled in the study were non-hospitalized individuals referred to the Cardiac Catheterization Laboratory for clinically indicated diagnostic procedures. Inclusion criteria were: (1) age 21–75; (2) ejection fraction >55% for normal left ventricular function group and ≤40% for left ventricular dysfunction group; (3) normal sinus rhythm; and (4) no digoxin therapy in at least 3 months. Exclusion criteria were: (1) insulin-requiring diabetes; (2) untreated hypertension; (3) myocardial infarction or unstable angina within 30 days of the procedure; (4) serum creatinine >2.0 mg dl–1; (5) inability to provide informed consent. The investigation was approved by the Mayo Foundation Institutional Review Board.

Thirty patients met criteria: 10 patients with normal left ventricular systolic function and 20 patients with evidence of left ventricular systolic dysfunction (LVD) by radionuclide angiography, left ventriculography or echocardiography.

All patients recruited to the protocol had cardiac medications (calcium channel antagonists, angiotensin converting enzyme inhibitors, beta-blockers and diuretics) held at least 12 h prior to the initiation of the study. The study protocol was completed in each patient prior to angiography.

2.2. Study protocol
2.2.1. Baseline measurements
Patients fasted after midnight in preparation for the procedure. Prior to the initiation of the study protocol a flow-directed balloon-tipped thermodilution pulmonary artery catheter was introduced percutaneously into the right internal jugular vein or femoral vein and advanced to a main pulmonary artery. Femoral artery and vein catheters were inserted percutaneously for hemodynamic monitoring and blood collection. Pressure measurements were obtained from the right atrium and main pulmonary artery, and pulmonary artery wedge pressure (PAWP) was determined after balloon inflation. PAWP position was confirmed by pressure tracing, O2 saturation >90%, and fluoroscopy. Cardiac index (CI) was calculated by standard thermodilution methodology. Eight milliliters of blood were withdrawn for ANP plasma assay from the pulmonary artery and femoral vein catheters. All initial hemodynamic measurements and blood specimens were obtained after 20 min of quiet rest in the supine position.

Following completion of the initial baseline supine measurements, a 10-min period of leg elevation (60 cm above the heart level) was undertaken. Leg elevation increases central blood volume which results in elevation of atrial pressures [5]. Leg elevation has been shown to result in increased plasma ANP concentration within 7 min [6]. After completion of the 10-min period of leg elevation, hemodynamic measurements and blood samples were again obtained from the same sites. The supine and leg elevation measurements prior to digitalis administration constituted the baseline measurements.

2.2.2. Digitalis administration
After the baseline hemodynamic measurements and blood samples were obtained, each patient received a standard dose of deslanoside (0.02 mg kg–1) administered intravenously over 10 min. After a 40-min drug equilibration period, each patient underwent the same data collection protocol in the supine position and with leg elevation as described for baseline measurements. Plasma concentrations of {alpha}-human ANP were determined after extraction by a specific radio-immunoassay as previously described by our laboratory [3].

2.3. Statistical analysis
Values were expressed as means±S.D. with statistical significance judged if the P-value was ≤0.05. Changes in hemodynamic variables were evaluated using paired t-tests. Comparisons between groups were performed using two sample t-tests. Paired t-tests were used to assess baseline vs. post-digitalis administration data and Spearman correlation coefficients and P-values were determined. Because of non-normality in the data, non-parametric Spearman correlation coefficients were used.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations of the...
 6. Conclusions
 References
 
3.1. Clinical characteristics
Table 1 presents characteristics for the two patient groups studied. Mean age was similar in the two groups (50 and 53 years). Left ventricular ejection fraction was 77±10% in the normal LV function group and 22±8% (P<0.0001) in the patient groups with heart failure. Of heart failure patients 75% were NYHA functional class status III/IV. The etiology of heart failure was non-ischemic dilated cardiomyopathy in 15 patients and ischemic cardiomyopathy in five patients. Eight patients in the normal LV function group were being evaluated for suspected coronary artery disease and two for aortic valvular heart disease.


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  		Table 1 Baseline characteristics of patient groups

 
3.2. Hemodynamic findings in patients with normal LV function
3.2.1. Baseline: leg elevation vs. supine
Patients with normal LV function exhibited normal resting hemodynamics (Figs. 1 and 2). Leg elevation stress resulted in a significant increase in PAWP (11.1±3.7–12.7±3.4, P=0.008) and in mean pulmonary artery pressure (MPAP) (18.4±3.3–20.0±3.9, P=0.05). There were non-significant increases in mean arterial pressure (MAP), right atrial pressure (RAP), CI, and systemic vascular resistance (SVR) with leg elevation.


Figure 1
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  		Fig. 1 Right atrial pressure, mean pulmonary artery pressure, and pulmonary artery wedge pressure before and after intravenous digitalis administration in patients without systolic left ventricular dysfunction (N=10).

 


Figure 2
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  		Fig. 2 Mean arterial pressure, heart rate, cardiac index, and systemic vascular resistance before and after intravenous digitalis administration in patients without systolic left ventricular dysfunction (N=10).

 
3.2.2. Supine: digitalis vs. baseline
Following digitalis administration in the supine position there was a significant decrease in heart rate (72±5–65±8, P=0.02), MPAP (18.4±3.3–15.9±3.7, P=0.03), PAWP (11.1±3.7–9.2±2.9, P=0.04) and CI (3.3±0.8–3.1±0.6, P=0.04). SVR increased from 1278±482 to 1471±421 dyne s–1 cm–5 (P=0.03). There was no significant change in MAP or RAP.

3.2.3. Digitalis: leg elevation vs. supine
In contrast to the effects of leg elevation before digitalis administration, leg elevation stress after digitalis administration was characterized by significant increases in HR (65±8–69±8, P=0.02), CI (3.1±0.6–3.5±0.6 l min–1 m–2, P=0.0005) and MPAP (15.9±3.7–17.2±3.9, P=0.04) and a decrease in SVR (1471±421–1283±374 dyne s–1 cm–5, P=0.02). After digitalis treatment the stress of leg elevation did not result in an increase in RAP or PAWP.

3.3. Hemodynamic findings in patients with impaired LV function
3.3.1. Baseline LVD compared to normal LV function patients
At baseline in the supine position, MAP and RAP in patients with LVD were not significantly different from corresponding values in patients without LVD; however, the remainder of the hemodynamic parameters were consistent with LVD and significantly different from the normal group (HR 92±21 vs. 72±5, P=0.0006), MPAP (33.6±11.6 vs. 18.4±3.3 mmHg, P<0.0001), PAWP (23.1±10.4 vs. 11.1±3.7, P=0.002), SVR (1740±627 vs. 1278±482, P=0.002) and CI (2.3±0.8 vs. 3.3±0.8, P=0.002) (Figs. 3 and 4).


Figure 3
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  		Fig. 3 Right atrial pressure, mean pulmonary artery pressure, and pulmonary artery wedge before and after acute intravenous digitalis administration in patients with systolic left ventricular dysfunction (N=20).

 


Figure 4
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  		Fig. 4 Mean arterial pressure, heart rate, cardiac index, and systemic vascular resistance before and after intravenous digitalis administration in patients with systolic left ventricular dysfunction (N=20).

 
3.3.2. Baseline: leg elevation vs. supine
In LVD patients the stress of leg elevation significantly increased PAWP (23.1±10.4–25.9±11.2, P=0.002), RAP (11.6±5.7–12.8±5.4, P=0.013), and MPAP (33.6±11.6–35.6±12.5, P=0.004). Other hemodynamic parameters were not significantly altered.

3.3.3. Supine: digitalis vs. baseline
Digitalis treatment in the supine position was associated with significant reductions in the abnormally elevated hemodynamic parameters of the heart failure patients with decreases in RAP (11.6±5.7–9.0±3.8, P=0.003), MPAP (33.6±11.6–28.4±11.0, P=0.0001), PAWP (23.1±10.4–16.5±8.3, P=0.0001), and SVR (1740±627–1482±603, P=0.009). There was a concomitant significant increase in CI (2.3±0.8–2.9±0.8, P=0.0002) but no significant change in HR or MAP.

3.3.4. Digitalis: leg elevation vs. supine
After digitalis administration in LVD patients, leg elevation no longer produced hemodynamic deterioration; the beneficial effects of digitalis were sustained despite hemodynamic stress (Figs. 3 and 4). In particular, a comparison of PAWP during leg elevation before and after digitalis showed a significantly lower pressure after digitalis (25.9±11.2–17.2±8.9, P=0.0004).

In summary, patients with systolic LVD responded to acute digitalis administration with improved hemodynamics, resulting in reduced cardiac filling pressures and increased cardiac output; digitalis-related hemodynamic improvements were sustained even during the stress of leg elevation.

3.4. Atrial natriuretic peptide concentrations
Pulmonary artery and femoral vein ANP plasma concentrations (pg ml–1) before and after digitalis administration are shown in Figs. 5 and 6 for patients with normal LV function and impaired LV function. Patients with LVD had significantly higher plasma ANP concentrations than patients with normal left ventricular function (pulmonary artery: 149±95 vs. 30±14 pg ml–1, P<0.0001). Plasma ANP concentration was higher in the pulmonary artery than in the femoral vein (P=0.0001), an expected finding since ANP is released into the circulation by way of the coronary sinus.


Figure 5
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  		Fig. 5 Pulmonary artery atrial natriuretic peptide plasma concentrations before and after intravenous digitalis administration in patients with normal systolic left ventricular function and patients with left ventricular dysfunction.

 


Figure 6
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  		Fig. 6 Femoral vein atrial natriuretic peptide plasma concentrations before and after intravenous digitalis administration in patients with normal systolic left ventricular function and patients with left ventricular dysfunction.

 
Before digitalis administration, leg elevation did not result in significant changes in ANP concentration in patients with or without LVD (Figs. 5 and 6). This is noteworthy in the case of patients with LVD in whom leg elevation produced a significant increase in PAWP, a stimulus that would be expected to enhance ANP secretion.

Digitalis administration had no significant effect on supine ANP concentrations in either group (Figs. 5 and 6) although there was a borderline significant increase in supine pulmonary artery ANP concentrations in patients with LVD (134.5±89.2–167.7±134.5 pg ml–1, P=0.055). In contrast to pre-digitalis response to leg elevation, leg elevation following digitalis resulted in a non-significant increase in pulmonary artery plasma ANP concentrations in patients with normal LV function and a statistically significant increase with impaired LV function (normal LV: 30±7–39±21 pg ml–1 (P=0.16); LVD: 157±129–188±170 pg ml–1 (P=0.03). This response of higher post-digitalis ANP concentration is noteworthy in that it occurred in association with reduced cardiac filling pressures (RAP, PAWP), reduced SVR and increased CI, i.e. directional hemodynamic changes that would be expected to be associated with lower ANP concentration. The increasing pulmonary artery ANP concentrations were directionally concordant in both groups and are in contrast to the decreased pulmonary artery ANP concentrations observed during leg elevation before digitalis. Femoral vein ANP concentrations were lower than pulmonary artery concentrations but demonstrated similar directional changes in both patient groups.

3.5. Prediction of hemodynamic response to digitalis
The hemodynamic responses to digitalis administration were most favorable in the setting of significantly elevated cardiac filling pressures and plasma ANP concentrations. Fig. 7 depicts the relationship between baseline PAWP and the change in PAWP observed after digitalis; patients with elevated baseline PAWP, e.g. ≥12 mmHg, had a decrease in PAWP after digitalis administration whereas patients with normal PAWP had little change in PAWP after digitalis (Spearman correlation coefficient, r=–0.7, P=0.0001). Plasma ANP concentrations were elevated in patients with increased ventricular filling pressures; in Table 2 the relationship between plasma ANP and the hemodynamic response to digitalis is shown. The post-digitalis change in hemodynamic measurements (digitalis treatment — baseline) for MPAP, PAWP and CI demonstrate statistically significant negative correlations for MPAP and PAWP with pulmonary artery and femoral vein plasma ANP concentrations, and a positive correlation for CI with plasma ANP concentrations. This demonstrates that elevated plasma ANP concentration is a strong predictor of a hemodynamically favorable response to acute digitalis administration. This relationship is illustrated in Fig. 8 where the effect of digitalis to lower PAWP is greatest in patients with elevated FV ANP concentrations (r=–0.61, P=0.004). The PAWP lowering effect of digitalis is maximal in the setting of elevated PAWP such as occurs in heart failure.


Figure 7
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  		Fig. 7 Relation of baseline pulmonary artery wedge pressure to change in pulmonary artery wedge pressure in response to digitalis administration in patients with and without systolic left ventricular dysfunction.

 


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  		Table 2 Correlation of change in hemodynamic response to acute digitalis administration with baseline plasma ANP (supine, combined normal and impaired LV function)

 


Figure 8
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  		Fig. 8 Relation of baseline femoral vein atrial natriuretic peptide plasma concentrations to change pulmonary artery wedge pressure in response to digitalis administration in both patients with and without systolic left ventricular dysfunction.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations of the...
 6. Conclusions
 References
 
Historical studies of digitalis in the treatment of heart failure suggested hemodynamic benefit, but were conducted in small numbers of patients with diverse heart failure etiologies and the evaluation of central hemodynamics in these studies was, by current standards, incomplete. The results of this study demonstrate beneficial responses to acute digitalis administration in patients with left ventricular systolic dysfunction who underwent uniform hemodynamic evaluation. They underscore the positive correlation between plasma ANP concentration and cardiac filling pressures and show for the first time that elevated plasma ANP concentration identifies patients in whom acute digitalis administration is most likely to result in hemodynamic improvement. The findings also suggest that digitalis may exert some of its beneficial effects by directly enhancing cardiac ANP release. The evidence of this study, therefore, supports the use of digitalis glycosides in the management of acute heart failure and may provide additional insight into a mechanism of action for digitalis therapy.

4.1. Digitalis and normal left ventricular systolic function
The assessment of acute digitalis administration in patients with normal left ventricular systolic function confirmed prior results and provides unique insight regarding the effects of leg elevation stress on cardiac hemodynamics prior to and after digitalis administration. However, our study patients were more uniform in etiology of heart failure and underwent a more comprehensive hemodynamic evaluation than previously reported. In subjects with normal ventricular systolic function, digitalis glycosides have been reported to increase systemic and coronary vascular resistances [7,8]. Digitalis administration in our patients with normal ventricular function significantly increased SVR with associated reductions in CI, heart rate, MPAP, and PAWP.

Our data show that in patients with normal left ventricular function the hemodynamic pertubation of leg elevation resulted in increased PAWP and MPAP. In contrast, after digitalis administration leg elevation in patients with normal ventricular function did not result in increased SVR, but rather SVR, CI and heart rate were restored to baseline pre-digitalis supine levels. After digitalis PAWP was maintained at a significantly reduced level even with leg elevation stress.

These findings suggest that digitalis exerts mildly negative hemodynamic effects in patients with normal ventricular systolic function at rest. When the stress of leg elevation was applied in the normal ventricular function group after digitalis, there was a restoration of HR, SVR and CI to baseline. The observed effects of leg elevation in patients with normal ventricular function reflect the action of intact baroreceptors and further suggests an effect of digitalis administration to enhance baroreceptor sensitivity. While digitalis has been reported to restore baroreceptor sensitivity and reduce cardiac sympathetic activity [9–12] in patients with heart failure after digitalis administration, our data suggests that digitalis therapy may enhance baroreceptor activity in the absence of chronic heart failure.

4.2. Hemodynamic effects of digitalis in left ventricular systolic dysfunction
Several previous investigations have shown hemodynamic responses to digitalis administration in humans with heart failure; some report favorable hemodynamic responses [13–19] while others show hemodynamic responses to be absent or inconsistent [20–23]. In the present study of well-characterized and uniformly studied patients, the hemodynamic response to acute intravenous digitalis treatment was determined in well-defined ventricular systolic dysfunction. Digitalis administration produced reductions in SVR and cardiac filling pressures, an increase in CI, but no change in the heart rate or mean arterial pressure. Similar findings have been reported by other investigators [14]. In the current study, however, the provocative hemodynamic maneuver of leg elevation was performed and resulted in further elevation of an already abnormally increased PAWP. Digitalis administration, however, not only improved all the baseline hemodynamic parameters but also prevented the potentially deleterious deterioration in heart failure hemodynamics during leg elevation stress, in particular preventing a further elevation in PAWP.

4.3. Digitalis and plasma ANP
Elevated ANP plasma concentrations are recognized to occur in patients with heart failure [6]. The results of our study confirm these observations. Furthermore, we show for the first time that increased plasma ANP concentration identifies patients who demonstrate the greatest beneficial hemodynamic response to digitalis.

Atrial pressure is a major determinant of plasma ANP concentration [6]. Administration of digitalis in our patients with systolic LVD resulted in significant reductions in PAWP, MPAP, RAP and SVR, constituting a favorable hemodynamic response. Since atrial pressure is a major determinant of ANP secretion, the digitalis-induced decrease in filling pressure might be expected to be accompanied by a concomitant reduction in plasma ANP concentration. However, no decrease in plasma ANP concentration was observed; rather increased plasma ANP concentrations were demonstrated. This unexpected directional change in ANP concentration after digitalis may be relevant to prior studies that have provided experimental support for the concept that digitalis stimulates ANP release from cardiac myocytes [24,25]. Tsotamato et al. [26] reported an increase in ANP plasma concentrations 1 h after deslanoside (0.01 mg kg–1) infusion in 13 patients with heart failure with no digitalis-induced change in SVR or CI. Our results demonstrate decreased filling pressure in response to digitalis administration which were associated with sustained increases in plasma ANP concentrations in patients with LVD. These findings are compatible with the hypothesis that digitalis is a stimulus to ANP release.


   5. Limitations of the study
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
6. Conclusions
 References
 
The results of the current study are limited by sample size and this may have reduced the power to detect more subtle effects of digitalis on hemodynamics and ANP concentration. The study design was to assess the acute effects of digitalis administration and these results may not be generalized to the chronic effects of digitalis therapy. Only patients with ventricular systolic dysfunction were evaluated and, therefore, digitalis effects on diastolic function cannot be assessed from these results. Drug therapy prior to the study may be expected to affect hemodynamic responses to acute digitalis treatment. However, at the time the patients were recruited to participate in this study protocol only nine patients with left ventricular dysfunction and 1 patient with normal left ventricular function were receiving an established medical regimen of short-acting CEI. Also, one patient with normal left ventricular function was receiving short-acting beta-blocker therapy. These medications were held at least 12 h before the study began and it would not be anticipated that such prior drug therapy would have a significant impact on hemodynamic responses to acute digitalis administration and none were detected.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusions
References
 
The findings of this study support a hypothesis that acute digitalis administration in patients with systolic LVD contributes to reductions in PAWP, MPAP, RAP and SVR and increases in CI. Increased cardiac filling pressure and increased plasma ANP concentration are highly predictive of a favorable hemodynamic response to digitalis glycoside administration. Our data are consistent with the concept that digitalis stimulates ANP release. Further studies, however, are needed to determine if plasma ANP concentration predicts long-term benefits of digitalis therapy.


   Acknowledgements
 
The authors wish to thank Darlene Albrecht for her expertise and meticulous care in preparing this manuscript for publication.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusions
 References
 

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J. G.F. Cleland and K. Goode
Natriuretic peptides for heart failure. Fashionable? Useful? Necessary?
Eur J Heart Fail, March 15, 2004; 6(3): 253 - 255.
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