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European Journal of Heart Failure 2007 9(6-7):674-677; doi:10.1016/j.ejheart.2007.01.008
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© 2007 European Society of Cardiology

Chronic sildenafil lowers transpulmonary gradient and improves cardiac output allowing successful heart transplantation

Andrew Jabbour*, Anne Keogh, Christopher Hayward and Peter Macdonald

Heart Transplant Unit, St Vincent's Hospital, Sydney, New South Wales, 2010, Australia

* Corresponding author. Cardiology Department, Level 4 Xavier Building, St Vincent's Hospital, Sydney, New South Wales, 2010, Australia. Tel: +61 2 83821111; fax: +61 2 83823084. E-mail address: jabbourandrew{at}hotmail.com


   Abstract
Top
 Notes
 Abstract
1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Introduction: For patients undergoing heart transplantation, an elevated pulmonary vascular resistance (PVR) increases mortality in the early post-heart transplant period. This study aimed to assess the effects of chronic sildenafil administration on the PVR, transpulmonary gradient (TPG), and cardiac output (CO) in patients with heart failure awaiting heart transplantation.

Method: The data from serial right heart catheterizations (RHC) of six patients were analyzed. All patients demonstrated a reaction to the vasodilators glyceryl trinitrate or inhaled iloprost at initial RHC before commencing sildenafil. A follow-up RHC was performed as required to guide management.

Results: The average total daily dose of sildenafil was 100 mg for a period of 68±58 days (4–145). The average TPG at baseline was 23.7 mmHg and fell in 4 of the 6 patients (67%) with an average reduction of 4.5±7.3 mmHg (–5 to 14). The average PVR at baseline was 571 dyn s cm–5 and fell in 5 of 6 patients (83%), with an average reduction of 167±266 dyn s cm–5 (74–518). The CO at baseline was 3.95 L/min and rose in 5 of 6 patients (83%) with an average improvement of 0.58 L/min (–1.1 to 1.3). The mean pulmonary capillary wedge pressure (MPCWP) at baseline was 26.3 mmHg and fell in 5 of 6 patients (83%) with an average fall of 5.5 mmHg (–1 to 17). Four of the six patients achieved a final TPG<15 mmHg, which we consider to be acceptable for orthotopic heart transplantation, average 11 mmHg (8 to 13). Three of these patients have already undergone successful, uncomplicated heart transplantation.

Conclusion: Chronic sildenafil use is safe and effective in reducing an elevated TPG and PVR in patients with heart failure requiring heart transplantation and allows patients to be transplanted who may otherwise have been excluded because of pulmonary hypertension.

Key Words: Heart failure • Pulmonary hypertension • Heart transplantation • Phosphodiesterase inhibitor • Sildenafil

Received June 26, 2006; Revised December 5, 2006; Accepted January 11, 2007


   1. Background
Top
 Notes
 Abstract
 1. Background
2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Secondary pulmonary hypertension is a common complication of chronic heart failure [1]. For patients undergoing heart transplantation, elevated pulmonary vascular resistance increases mortality in the early post-heart transplant setting unless balanced by a donor: recipient weight advantage [2,3]. This has lead to the assessment of pulmonary arterial reaction to vasodilators prior to heart transplantation, to select those patients who are more likely to survive the consequent right heart strain after heart transplantation and also to indicate which agents might be useful in their post-operative management. Traditional haemodynamic challenge agents include inhaled nitric oxide, inhaled iloprost, intravenous nitroglycerine, or intravenous sodium nitroprusside during right heart catheterization (RHC). More recently the phosphodiesterase-5 inhibitor sildenafil has also been shown to decrease pulmonary vascular resistance (PVR) in patients with heart failure when given as a single dose [4,5].

Sildenafil has been shown to increase exercise capacity in healthy mountaineers in hypoxic states [6]. It causes preferential pulmonary vasodilation in patients with primary pulmonary hypertension and improves gas exchange in an acute setting in severe pulmonary fibrosis [7]. It has also been shown to increase endothelium dependant, flow-mediated vasodilation in patients with chronic heart failure when compared to placebo [8].

Oral sildenafil has also been used in post-heart transplantation to lower PVR and improve right heart failure [9]. No data however exist regarding its chronic use in patients with severe heart failure.


   2. Aims
Top
 Notes
 Abstract
 1. Background
 2. Aims
3. Materials and methods
 4. Results
 5. Conclusion
 References
 
In this case series we describe the effects of chronic sildenafil administration on the transpulmonary gradient (TPG), PVR and cardiac output (CO) in 6 patients with heart failure waiting for heart transplantation.


   3. Materials and methods
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
4. Results
 5. Conclusion
 References
 
3.1. Inclusion and exclusion criteria
All patients had a severe cardiomyopathy and were on a heart transplant waiting list. They all had to have a TPG>15 mmHg after vasodilator challenge, and were all considered high risk cases. All patients demonstrated a vasodilatory reaction to nitrates or inhaled iloprost at initial right heart catheterization.

3.2. Patient parameters
Six patients were studied (one female, five male, average age 50, range 44-58). Four of the six patients had an ischaemic cardiomyopathy and two had an idiopathic dilated cardiomyopathy. All patients were on standard heart failure medications, which were maintained unchanged during the study and included angiotensin converting enzyme inhibitors, beta blockers and spironolactone.

3.3. Right heart catheterization
The data from serial RHC were studied. Catheterization was performed in the non-fasting state, after the patients' usual morning medications including sildenafil. A follow-up RHC was then performed as required according to clinical urgency to guide management. The main haemodynamic outcome measures were central venous pressure, mean pulmonary artery pressure, PVR, TPG, MPCWP, systemic arterial pressure and vascular resistance, and CO (via thermodilution).

3.4. Sildenafil therapy
Patients had nitrates discontinued at the commencement of the study and were started on sildenafil (Viagra®) after the initial RHC. The starting dose was 12.5 mg three times daily (tid) which was up titrated to 25-50 mg tid over several weeks as tolerated. The patient was then followed as frequently as deemed necessary by the treating physician.


   4. Results
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
5. Conclusion
 References
 
Two patients received sildenafil at a dose of 50 mg tid, and 4 patients at 25 mg tid. The time to follow up RHC was 68±58 days (4-145). No side effects were reported. The TPG was reduced in 4 of the 6 patients (67%) with an average reduction of 4.5±7.3 mmHg (–5 to 14) (Fig. 1). The PVR fell in 5 of 6 patients (83%), with an average reduction of 167±266 dyn s cm–5 (74-518) (Fig. 2). The cardiac output rose in 5 of 6 patients (83%) with an average improvement of 0.58 L/min (–1.1 to 1.3) (Fig. 3) and the mean pulmonary capillary wedge pressure fell in 5 of 6 patients (83%) with an average fall of 5.5 mmHg (–1 to 17). The systemic blood pressure fell by an average of 10.6 mmHg, and the systemic vascular resistance fell by an average of 257 dyn s cm–5.


Figure 01
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  		Fig. 1 Transpulmonary gradient.

 


Figure 02
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  		Fig. 2 Pulmonary vascular resistance.

 


Figure 03
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  		Fig. 3 Cardiac output.

 
Two of the six patients had a TPG≤10 mmHg at a follow-up RHC. The TPG in the other four patients was reduced but still >17 mmHg at a follow up. Three of these patients were challenged with either inhaled iloprost (n=1), intravenous sodium nitroprusside (n=–1), or intravenous glyceryl trinitrate (n=1) (the latter without symptomatic hypotension). The cumulative effect of chronic sildenafil and acute challenge in the six patients was an average TPG reduction of 9.6±11.5 mmHg (7 to 17), and an average PVR reduction of 289±400 dyn s cm–5 (–219 to 722). Four of the six patients achieved a final TPG<15 mmHg, which we consider to be acceptable for orthotopic heart transplantation, average 11 mmHg (8 to 13). Three of these patients have already undergone successful heart transplantation, and one is waiting. Sildenafil was continued for 2 to 3 month post-transplant to allow time for the right ventricle to remodel, with no cases experiencing right heart failure or need for an assist device.


   5. Conclusion
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
References
 
We have demonstrated that chronic sildenafil use is safe and effective in reducing an elevated TPG and PVR in patients with class IV heart failure requiring heart transplantation and allows patients to be transplanted who may otherwise have been excluded because of pulmonary hypertension. Sildenafil was associated with a fall in PCWP in 83% of patients, and for this reason it is preferable to inhaled nitric oxide, which is often used post-heart transplant, but which may precipitate pulmonary oedema in patients with advanced heart failure. We suggest that patients with an elevated TPG requiring heart transplantation be given a trial of long term sildenafil and be reassessed with acute vasodilator challenge prior to excluding them from listing.

The observation of an improved cardiac output with chronic sildenafil use is of importance. Sildenafil has already been shown to decrease aortic systolic and diastolic pressure with reduced wave reflection on arterial tonometry, and to improve arterial stiffening and cardiac loading [10]. Borlaug et al. postulated that the blunting of beta adrenergic stimulation by sildenafil may be beneficial in heart failure where neurohormonal stimulation is enhanced [11]. The improved cardiac output and reduced wedge pressure in our series provides evidence in support of this hypothesis. Acknowledging the limitations of data collected from this pilot series, a randomized, cross over trial exploring the value of sildenafil in the broad population of patients with heart failure is currently underway.


   Acknowledgements
 
Many thanks to Drs Soren Mellemkjaer and Laurence Schneider for their advice in data interpretation.


   Notes
Top
 Notes
Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
{star} All the work was performed at St Vincent's Hospital, Sydney, New South Wales, Australia.


   References
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 

  1. Hosenpud J.D., Bennett L.E., Keck B.M., Boucek M.M., Novick R.J. The registry of the international society for heart and lung transplantation: seventeenth official report—2000. J Heart Lung Transplant (2000) 19:909–931.[CrossRef][Web of Science][Medline]
  2. Murali S., Kormos R.L., Uretsky B.F., et al. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: the Pittsburgh experience. Am Heart J (1993) 126:896–904.[CrossRef][Web of Science][Medline]
  3. Chen J.M., Levin H.R., Michler R.E., Prusmack C.J., Rose E.A., Aaronson K.D. Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality. J Thorac Cardiovasc Surg (1997) 114:627–634.[Abstract/Free Full Text]
  4. Alaeddini J., Uber P.A., Park M.H., Scott R.L., Ventura H.O., Mehra M.R. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am J Cardiol (Dec 1 2004) 94(11):1475–1477.[CrossRef]
  5. Angel Gomez-Sanchez M., Saenz De La Calzada C., Escribano Subias P., et al. Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation. Eur J Heart Fail (Aug 2004) 6(5):615–617.[Abstract/Free Full Text]
  6. Ghofrani H.A., Reichenberger F., Kohstall M.G., et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest Base Camp. Ann Intern Med (2004) 141:169–177.[Abstract/Free Full Text]
  7. Ghofrani H.A., Wiedemann R., Rose F., et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet (2002) 895–900.
  8. Katz S.D., Balidemaj K., Homma S., et al. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol (2000) 845–851.
  9. Aparna Kulkarni M.D., Tajinder P., Singh M.D., et al. Sildenafil for pulmonary hypertension after heart transplantation. J Heart Lung Transplant (2004) 23:1441–1444.[CrossRef][Web of Science][Medline]
  10. Hirata K., Adji A., Vlachopoulos C., O'Rourke M. Effect of sildenafil on cardiac paerformance in patients with heart failure. Am J Cardiol (2005) 96:1436–1440.[CrossRef][Web of Science][Medline]
  11. Bourlaug B.A., Melenovsky V., Marhin T., Fitzgerald P., Kass D.A. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation (2005) 112:2642–2649.[Abstract/Free Full Text]

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