Skip Navigation

European Journal of Heart Failure 2004 6(5):615-617; doi:10.1016/j.ejheart.2003.11.015
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gómez-Sánchez, M. A.
Right arrow Articles by Calvo, L. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gómez-Sánchez, M. A.
Right arrow Articles by Calvo, L. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2004 European Society of Cardiology

Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation

Miguel Angel Gómez-Sánchez*, Carlos Saenz de la Calzada, Pilar Escribano Subías, Juan Francisco Delgado Jiménez, María Lázaro Salvador, Agustín Albarrán González and Luis Cea Calvo

Heart Failure and Pulmonary Hypertension Unit, Cardiology Department, Hospital Universitario Doce de Octubre Avda de Cordoba s/n, Madrid, Spain

* Corresponding author. Tel.: +34-91-3908677; Fax: +34-91-3908669.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Objective: To determine the acute vasodilator effect of sublingual sildenafil in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD).

Background: Pulmonary hypertension confers an increased risk of early graft failure.

Patients and methods: Seven patients, (mean age of 53±8) with severe LVD (mean EF: 19±1.7%, functional class III–IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. Sublingual sildenafil was given without changing the previous treatment of heart failure.

Results: After 30 min of sublingual sildenafil, mPAP decreased from 37 (28–61) to 30 (16–42) mmHg and PVR decreased from 5.2 (1.9–13.8) to 2.5 (1.4–3.9) W.U. after 45 min. Mean TPG decreased from 19 (16–33) to 12 (8–14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. Sublingual sildenafil was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2.

Conclusions: Based on this initial study, sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results.

Key Words: Sildenafil • Pulmonary hypertension • Heart transplant

Received November 8, 2002; Revised October 10, 2003; Accepted November 30, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Increased pulmonary vascular resistance (PVR), usually denoted by pulmonary artery hypertension (PH), has been identified as an independent predictor of mortality in heart transplant candidates [1–3]. The ISLHT data [4] indicate that PVR correlates in a linear fashion with mortality after heart transplantation (HTx).

Thus, evaluation of fixed or reversible components of PH is crucial to reduce such complications. Nitroprussiate, dobutamine, prostacyclin and other vasodilators are used for this purpose after a period of tailored therapy for heart failure. Our objective in this exploratory uncontrolled study was to determine the acute vasodilator effect of sublingual sildenafil in severe PH due to severe LVD in HTx candidates.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Seven male patients, mean age of 53±8 years with severe LVD (mean EF: 19±1.7% and NYHA functional class III–IV) due to dilated cardiomyopathy (4 idiopathic, 2 coronary artery disease and 1 valvulopathy), were evaluated for HTx. All patients presented a mean TPG >12 mmHg and PVR >2.5 W.U., despite treatment with furosemide (51±16 mg), dobutamine (11±1.3 mcg/kg/min), oral enalapril (14±5 mg) or losartán (42±14 mg), carvedilol (16±13 mg), spironolactone (25 mg) and digoxin (0.22±0.05 mg).

The following hemodynamic data were obtained in all patients: Right atrial pressure, mPAP, mean pulmonary capillary wedge pressures, mean TPG, PVR, arm cuff blood pressure (systolic/diastolic/mean), cardiac output (by thermodilution technique) and systemic vascular resistances. Hemodynamic data were obtained at basal state and then 15, 30 and 45 min after 100 mg of sublingual sildenafil administration, standard therapy for heart failure was maintained. The sildenafil regimen was based on previous reports of its use in arterial PH [5–7] and heart failure [8]. Written consent was obtained for all patients. The study was approved by our Institutional Clinical Investigation Board.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
The hemodynamic variables are shown as median values and range. The statistical significance of overall differences was estimated with Friedman test (non-parametric repeated measures ANOVA). When appropriate after Friedman's test, the differences between the values of measurements carried out at definite times after dosing and corresponding baseline values were evaluated by Dunn's test. The alpha level was set at 0.05. The analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, NC, USA) and GraphPad InStat version 3.00 (GraphPad Software, San Diego, CA, USA).


   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
Detailed hemodynamic data are presented in the Table 1. Overall statistically significant differences were observed for mPAP, mean TPG and PVR. Multiple comparisons analysis identified statistical differences between basal values and values at 30 min (mPAP) and 45 min (PVR and mTPG). Sublingual sildenafil was well tolerated, with only transient facial flushing in four patients and mild headache in two.


View this table:
[in this window]
[in a new window]

  		Table 1 Hemodynamic results after 100 mg of sublingual sildenafil

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
Recent reports, where oral sildenafil had resulted in improvement of severe primary PH [5,6,8] and congestive heart failure [8], prompted us to use sildenafil as here described.

The main finding of this initial study is that sublingual sildenafil causes a rapid and selective decrease in mTPG, mPAP and PVR in HTx patients with PH due to left ventricular systolic dysfunction, without significant changes in mean pulmonary wedge pressure, cardiac output and systemic vascular resistances. To the best of our knowledge, this is the first hemodynamically documented report on the usefulness of sublingual sildenafil as a simple acute vasodilatory test in HT candidates with PH.

Sildenafil citrate is a selective inhibitor of phosphodiesterase type 5 (PDE5), responsible for cGMP degradation, producing corpus cavernosum smooth muscle relaxation, but is also found in pulmonary vascular smooth muscle [9]. This may explain why sublingual sildenafil produces a selective response in the pulmonary vessel without significant changes in left heart hemodynamic variables. Highest blood levels of sildenafil are reached within 30–120 min (mean: 60 min) after oral administration, followed by a progressive decline over the next 12 h [10]. It is important to emphasize that all of our patients, were receiving intensive standard therapy for advanced heart failure prior to sublingual sildenafil administration. Therefore it remains unknown whether sublingual sildenafil would have the same beneficial effects in the absence of such concomitant heart failure treatment.

Based on this initial study, we believe sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in HTx candidates with PH secondary to severe LVD. Nevertheless, further studies are warranted to confirm our results.


   Acknowledgements
 
We gratefully acknowledge Dr Javier de la Cruz Bértolo (Clinical Epidemiology Unit), for excellent assistance in statistical analysis.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 

  1. Erickson K.W., Constanzo-Nordin M.R., O'Sullivan E.J., Johnson M.R., Zucker M.J., Pifarré R., et al. Influence of preoperative transpulmonary gradient on late mortality after orthotopic heart transplantation. J Heart Lung Transpl (1990) 9:526–537.
  2. Costard-Jäckle A., Fowler M.B. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol (1992) 19:48–54.[Abstract]
  3. Delgado J.F., Gómez Sánchez M.A., Saenz de la Calzada C., Sanchez V., Escribano P., Hernandez-Afonso J., et al. Impact of mild pulmonary hypertension on mortality and pulmonary artery pressure profile after heart transplantation. J Heart Lung Transpl (2001) 20:942–948.[CrossRef][Web of Science][Medline]
  4. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ, The Registry of the International Society of Heart and Lung Transplantation: seventeenth official report-2000. J Heart Lung Transplant 2000;19: 909–931.
  5. Prasad S., Wilkinson J., Gatzoulis M.A. Sildenafil in primary pulmonary hypertension. New Engl J Med (2000) 343:1342.[Free Full Text]
  6. Wilkens H., Guth A., König J., Forestier N., Cremers B., Hennen B., et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation (2001) 104:1218–1222.[Abstract/Free Full Text]
  7. Ghofrani H.A., Wiedemann R., Rose F., Olschewski H., Schermuly R.T., Weissmann N., et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med (2002) 136:512–522.
  8. Bocchi E.A., Guimarâes G., Mocelin A., Bacal F., Bellotti G., Ramires J.F. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure. A double blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation. (2002) 106:1097–1103.[Abstract/Free Full Text]
  9. Jackson G., Benjamin N., Jackson N., Allen M.J. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol (1999) 83:13C–20C.[Web of Science][Medline]
  10. Walker D.K., Ackland M.J., James G.C., Muirheads G.J., Rance D.J., Wastall P., et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica (1999) 29:297–310.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur J Heart FailHome page
A. Jabbour, A. Keogh, C. Hayward, and P. Macdonald
Chronic sildenafil lowers transpulmonary gradient and improves cardiac output allowing successful heart transplantation
Eur J Heart Fail, June 1, 2007; 9(6-7): 674 - 677.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
A. Al-Hesayen, J. S. Floras, and J. D. Parker
The effects of intravenous sildenafil on hemodynamics and cardiac sympathetic activity in chronic human heart failure
Eur J Heart Fail, December 1, 2006; 8(8): 864 - 868.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gómez-Sánchez, M. A.
Right arrow Articles by Calvo, L. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gómez-Sánchez, M. A.
Right arrow Articles by Calvo, L. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?