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European Journal of Heart Failure 2006 8(8):864-868; doi:10.1016/j.ejheart.2006.03.007
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© 2006 European Society of Cardiology

The effects of intravenous sildenafil on hemodynamics and cardiac sympathetic activity in chronic human heart failure

Abdul Al-Hesayen, John S. Floras and John D. Parker*

Division of Cardiology, Department of Medicine, Mount Sinai Hospital and University Health Network, University of Toronto Ontario, Canada M5G 1X5

* Corresponding author. Mount Sinai and University Health Network Hospitals, University of Toronto, 600 University Avenue, Suite 1609, Toronto, Ontario, Canada M5G 1X5. Tel.: +1 416 586 4794; fax: +1 416 586 8413. E-mail address: jdp{at}ca.inter.net


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Erectile dysfunction is common in patients with chronic heart failure and sildenafil is an effective treatment option in this population. Sildenafil has been reported to increase sympathetic outflow in normal volunteers. To date, experience with sildenafil in patients with congestive heart failure is limited and the impact of phosphodiesterase-5 inhibition on sympathetic activity in this population has not been evaluated.

Methods and results: 10 patients with heart failure (ejection fraction 23±3%) were studied. Generalized and cardiac sympathetic activity responses to an intravenous infusion of sildenafil were measured by the norepinephrine spillover method. In response to sildenafil, there was a significant reduction in mean pulmonary artery (– 26±5%, P<0.01) and mean arterial pressures (–8±1%, P<0.01). These hemodynamic responses were accompanied by a 22±5% reduction in cardiac norepinephrine spillover (P<0.02) but no change in total body norepinephrine spillover.

Conclusions: The acute administration of sildenafil is associated with a modest reduction in systemic arterial blood pressure and a more substantial reduction in pulmonary arterial pressure. These hemodynamic changes are observed in the absence of systemic sympathetic activation and are associated with a reduction in cardiac norepinephrine spillover in patients with chronic heart failure. These observations are relevant given the high prevalence of erectile dysfunction in this patient population.

Key Words: Autonomic nervous system • Heart failure • Sildenafil

Received September 14, 2005; Revised February 7, 2006; Accepted March 29, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Erectile dysfunction affects 60-70% of males attending heart failure clinics [1]. Sildenafil, a selective inhibitor of phosphodiesterase-5, is an effective therapy for erectile dysfunction in heart failure patients [1,2]. Despite this documented efficacy, there has been some concern about the safety of the use of phosphodiesterase-5 inhibitors in patients with severe cardiac disease. Initially this concern stemmed from reports in the lay press of adverse cardiovascular events including arrhythmias and death that were temporally related to sildenafil usage. These reports led some investigators to study the impact of sildenafil on the sympathetic nervous system. Phillips et al. described an increase in muscle sympathetic nerve activity in normal volunteers 1 h after oral administration of 100 mg of sildenafil [3]. The authors conclude that this sympathetic excitation in response to sildenafil might be associated with a risk of adverse events in patients with severe cardiovascular disease including heart failure. Evidence for cardiac sympathetic excitation following administration of sildenafil has been suggested by Piccirillo et al., who described an increase in sympathetic and a reduction in vagal modulation of sinus node discharge as measured by heart rate variability following the oral administration of sildenafil in patients with heart failure [4].

Importantly, data on the effects of sildenafil on cardiac filling pressures, pulmonary arterial pressures and cardiac output are limited in patients with congestive heart failure secondary to left ventricular systolic dysfunction. Furthermore, the impact of sildenafil administration on sympathetic activity directed towards the myocardium has also not been described. Therefore, the purpose of the current study was to document detailed hemodynamic and neurochemical responses to sildenafil in patients with moderate to severe congestive heart failure and to explore whether such administration is associated with the potential adverse effect of cardiac sympathetic activation.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patients
We studied patients with symptomatic chronic heart failure and left ventricular ejection fraction ≤40% who were referred for a diagnostic cardiac catheterization. None of the study subjects were receiving nitrate therapy.

All medications were held on the morning of the study. The protocol was approved by the Mount Sinai Hospital Research Ethics Board for experimentation involving human subjects and written informed consent was obtained from all subjects.

2.2. Hemodynamic and coronary flow measurements
A diagnostic left and right heart catheterization from the femoral approach was performed without sedation. After the diagnostic procedure, the pulmonary artery catheter was left in place. A 7F thermodilution catheter (type CCS-7U-90B, Webster Laboratories) was inserted from an antecubital vein and positioned in the coronary sinus under fluoroscopic guidance for flow measurements and blood sampling. Femoral artery pressure was monitored via a 6F side-arm sheath (Cordis Laboratories). Cardiac output was assessed by the Fick method. Coronary sinus blood flow measurements were performed in duplicate according to the method of Ganz et al. [5].

2.3. Norepinephrine spillover measurements
Sympathetic activity was estimated by the measurements of cardiac and total-body norepinephrine spillover according to the radiotracer technique of Esler et al. [6] For these measurements, tritiated norepinephrine (1.6 µCi/min with a 16-µCi priming bolus of L-[2,5,6-3H] norepinephrine; New England Nuclear) was infused into the femoral vein through a Harvard pump (model 33, Harvard Apparatus Canada) to steady-state concentration in plasma. Norepinephrine spillover rates were calculated as follows:


Formula



Formula

where [3H]NE indicates tritium-labeled norepinephrine; NEext, transcardiac fractional extraction of tritium-labeled norepinephrine; NEcs and NEart, coronary sinus and arterial plasma norepinephrine concentration, respectively, and CSPF, coronary sinus plasma flow.

2.4. Analysis of plasma catecholamines
Plasma catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Fractions from the high-performance liquid chromatography effluent containing tritium labeled norepinephrine were assayed by liquid scintillation spectroscopy [7,8]. The biochemical analysis was performed by personnel blinded to patient status.

2.5. Study protocol
After the stability of baseline hemodynamics was confirmed (2 measurements ≥10 min apart with <5% variation in mean pulmonary artery, and mean systemic arterial pressures, Table 1) control measurements were obtained. Subsequently, sildenafil was started and given as a 5-min bolus followed by a maintenance infusion. All subjects received an initial low dose comprised of a bolus of 0.5 mg/5 min followed by a maintenance infusion of 0.1 mg/15 min (low dose). At the end of 20 min, measurements of hemodynamics, and total-body and cardiac norepinephrine spillover were determined. Subsequently, at 20-min intervals the bolus was repeated and the infusion rate of sildenafil was increased until a 5% to 10% drop in mean systemic arterial pressure was observed. After the specified hemodynamic endpoint was achieved, the sildenafil infusion was maintained and cardiac and total-body norepinephrine spillover were measured 20 min later. To achieve this hemodynamic endpoint, a mean bolus dose of 2.4±0.2 mg and a mean maintenance dose of 0.7±0.1 mg was administered (high dose). Previous human studies have documented that this infusion rate is associated with a sildenafil plasma level of approximately 100 ng/ml (Pfizer data on file).


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  		Table 1 Hemodynamic responses to sildenafil

 
2.6. Statistical analysis
All data are presented as mean±SEM. The effects of sildenafil were assessed by 1-way repeated measures ANOVA with the use of Student-Newman-Keuls test for post hoc comparison. P< 0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Baseline characteristics
The study population consisted of 10 patients (9 men, 1 woman, mean age±SEM, 60±5 years, ejection fraction 23±3%). The etiology of heart failure was ischemic in 6 and dilated in 4 patients. All patients had New York Heart Association functional class III-IV symptoms. Medical therapy included an angiotensin converting enzyme inhibitor or angiotensin receptor antagonist (n=8), β-blocker (n=5), loop diuretic (n=10), spironolactone (n=7), and digoxin (n=7). The study subjects exhibited the hemodynamic characteristics of heart failure with elevated filling pressures and reduced cardiac index.

3.2. Hemodynamic responses to low dose sildenafil
Low dose sildenafil had a neutral hemodynamic effect with the exception of a significant reduction in right atrial pressure (–28±11%). (Table 1).

3.3. Hemodynamic responses to high dose sildenafil
Sildenafil caused a significant reduction in right atrial pressure (–45±6%, P<0.01), mean pulmonary artery pressure (–26±5%, P<0.01), and mean arterial pressure (–8±1%, P<0.01). Sildenafil reduced pulmonary capillary wedge pressure, however this reduction did not achieve statistical significance (–15±9%, P=0.16). There was a significant increase in cardiac index in response to sildenafil (+10±4%, P<0.02). Sildenafil effects were preferentially directed at the pulmonary circulation as reflected by a significant reduction in the pulmonary vascular to systemic vascular resistance ratio during the infusion (–13±3%, P<0.01). The hemodynamic effects of this sildenafil dose were significantly different from those observed with low dose sildenafil in all measured variables with the exception of the pulmonary capillary wedge pressure which did not change with either dose (Table 1).

3.4. Generalized and cardiac sympathetic system responses
Coronary sinus blood flow could not be measured in one subject for technical reasons. Low dose sildenafil had a neutral effect on total-body and cardiac norepinephrine spillover (Table 2). Despite the reduction in blood pressure with high dose sildenafil there was no change in total-body norepinephrine spillover. However, there was a significant reduction in cardiac norepinephrine spillover (–22±5%, P<0.02) (Table 2, Fig. 1).


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  		Table 2 Neurohormonal responses to sildenafil

 


Figure 1
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  		Fig. 1 Cardiac norepinephrine spillover (CANESP) at control (CNTR), low dose (LD), and high dose (HD) sildenafil infusion. *P<0.05 vs. CNTR, {dagger}P<0.05 vs. LD. Data are represented as mean±SEM.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The major findings of the present investigation are: (1) sildenafil caused a significant reduction in pulmonary artery and cardiac filling pressures with a modest reduction in systemic arterial pressure, and (2) these hemodynamic changes were accompanied by a reduction in cardiac norepinephrine spillover, a measure of cardiac efferent sympathetic activity.

Similar to the recent observations of other groups, we documented a significant reduction in right atrial and mean pulmonary arterial pressure with an accompanying increase in cardiac output [9,10]. The vasodilatory effects of sildenafil were preferentially directed at the pulmonary circulation. This observation is not surprising given the abundant expression of phosphodiesterase-5 in lung tissue [11]. Although the decrease in systemic vascular resistance may have played a role, the increase in cardiac index also serves to emphasize the importance of right ventricular unloading in heart failure patients and its potential favourable impact on diastolic ventricular interaction [12]. The relevance of this response is evident by the prognostic significance of right ventricular ejection fraction in heart failure patients [13]. This increase in cardiac index could be a marker of better short term prognosis [14].

High dose sildenafil was associated with a 20% reduction in cardiac norepinephrine spillover, a variable that is an independent predictor of mortality [15]. Three possible mechanisms for this observation can be suggested. First, nitric oxide (NO) is known to possess central sympathoinhibitory effects and sildenafil, by potentiating the biologic effects of NO, could reduce central sympathetic outflow [16,17]. Second, the prejunctional effects of NO on norepinephrine release could explain the cardiac sympathoinhibitory effect of sildenafil [18]. Finally, this selective cardiac sympathoinhibitory effect could be related to the cardiopulmonary baroreceptor unloading that occurred in response to sildenafil infusion. Multiple lines of evidence suggest that reductions in cardiac filling pressure in patients with heart failure secondary to dilated cardiomyopathy can lead to cardiac specific reductions in sympathetic activity [15,19,20]. Although the methods we employed do not allow us to determine the mechanism with certainty, it is reasonable to hypothesize that both the prejunctional sympathoinhibitory effects of NO and the indirect sympatholytic effects related to the unloading of cardiopulmonary receptors could explain the observed reduction in cardiac norepinephrine spillover.

Our findings might seem contradictory to those of Phillips et al. who described a 1.5 fold increase in muscle sympathetic activity in response to oral sildenafil in normal volunteers [3]. It is possible that the discordant results are related to differences in the populations studied in these two reports. Importantly, their report described the responses of the vascular sympathetic drive as measured by muscle sympathetic nerve activity. Our measures of total body and cardiac norepinephrine spillover reflect changes in generalized and cardiac specific norepinephrine release, indices that are not necessarily concordant with changes in efferent sympathetic nerve firing rate [21]. Furthermore, multiple studies have documented that there are important regional differences in sympathetic response [20-22]. As such, the observation that cardiac sympathetic responses are different from sympathetic responses directed at the skeletal muscle bed is not unexpected. Finally, multiple studies have documented that sympathetic responses to a variety of stimuli are different in the setting of heart failure as compared to those with normal cardiac function [22,23]. Similarly, our findings are not contradictory to those of Piccirillo et al. who described a reduction in heart rate variability in response to sildenafil in patients with heart failure [4]. Heart rate variability is a measure of vagal and sympathetic outflow directed at the sinoatrial node while cardiac norepinephrine spillover is a measure of sympathetic nerves firing rate directed at the left ventricular myocardium. Indeed, the non concordance of these measures to physiological intervention is not peculiar to our protocol and has been previously described [23].

It is important to consider the limitations of this study. We examined the acute effects of intravenous sildenafil; the long-term effects of sildenafil therapy on cardiac sympathetic activity in patients with heart failure cannot be inferred from the present study. However, our observations are helpful in documenting the safety of administering sildenafil acutely to patients with severe heart failure. Furthermore, based on these observations the hemodynamic and cardiac sympathetic effects of chronic sildenafil administration should be explored. It is also acknowledged that we did not study a parallel control group. Nevertheless, we do not believe that the observed cardiac sympathoinhibitory response is simply a reflection of the experimental model. Previous studies from our laboratory, using identical techniques, confirm that cardiac norepinephrine spillover does not change as a function of time in patients with heart failure secondary to dilated cardiomyopathy [7].

In conclusion, our study shows that acute sildenafil administration is associated with a preferential pulmonary vasodilatation with accompanying reduction in cardiac norepinephrine spillover in patients with chronic heart failure. These observations are relevant given the high prevalence of erectile dysfunction in this patient population. Furthermore, the effects of chronic sildenafil therapy warrant further investigation given the known deleterious effects of heightened cardiac sympathetic activity in the setting of heart failure.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This study was funded by an operating grant from the Heart and Stroke Foundation of Ontario (grant T-3696), Pfizer Canada, and Bayer Inc. The authors wish to thank the staff of the Bayer Cardiovascular Clinical Research Laboratory of Mount Sinai Hospital for their help in the completion of these studies.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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