European Heart Journal Advance Access originally published online on June 4, 2008
European Heart Journal 2008 29(13):1681-1687; doi:10.1093/eurheartj/ehn215
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Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients
Pediatric Cardiology and Adult Congenital Unit, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
Received 22 August 2007; revised 22 April 2008; accepted 6 May 2008; online publish-ahead-of-print 4 June 2008.
* Corresponding author. Tel: +39 051 6363435, Fax: +39 051 6363461, Email: alessandro5574{at}iol.it
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Abstract |
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Aims: We sought to assess the effects of sildenafil on exercise capacity and haemodynamic response to exercise in Fontan patients.
Methods and results: We prospectively studied 27 patients with Fontan circulation (age 22.8 ± 4.9 years). All patients underwent a baseline exercise test with non-invasive measurement of cardiac index (CI) and pulmonary blood flow (PBF) index, and peak exercise oxygen uptake (VO2). After the baseline test, patients were randomly assigned to receive either a single 0.7 mg/kg body weight oral dose of sildenafil citrate (n = 18) or no treatment (control group, n = 9). After 1 h of rest, all patients performed a second exercise test. All patients completed the study protocol. The dose of sildenafil ranged from 25 to 50 mg. The change in peak VO2, the primary endpoint, was greater in the sildenafil group (9.4 ± 5.2%) than in the control group (0.3 ± 4.1%, P < 0.05). Sildenafil increased rest and peak exercise PBF index (P < 0.01 and P < 0.05 vs. control group, respectively), as well as rest and peak exercise CI (P < 0.001 and P < 0.05 vs. control group, respectively), without altering rest or peak exercise transcutaneous arterial blood oxygen saturations (P > 0.05 vs. control group for both). No patient reported serious adverse events after sildenafil.
Conclusion: In Fontan patients, oral administration of a single dose of sildenafil improves exercise capacity and haemodynamic response to exercise.
Key Words: Fontan • Cardiac output • Oxygen uptake • Exercise
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Introduction |
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Although the Fontan operation has contributed greatly to the improvement of mortality rate in patients with a single ventricle,1,2 recent studies have emphasized a continuing risk of late failure and poor functional outcome in some long-term survivors.3,4 Decreased exercise tolerance and abnormal haemodynamic response to stress have also been clearly recognized in patients after this procedure.5,6 These results strongly suggest fundamental limitations inherent in Fontan physiology.7 The limitations are related to increased afterload7,8 and reduced ventricular filling capacity with subsequent limited preload reserve,8,9 especially during conditions associated with the increased heart rate (HR), e.g. exercise.
It has been suggested that reduced preload reserve might be related to the lack of pulmonary ventricular energy propelling venous blood flow into the ‘single ventricle’.7 Furthermore, Fontan patients may have a pulmonary vascular dysfunction,10 with blunted release of endothelium-derived nitric oxide (NO). This is consequent to the loss of flow pulsatility in the Fontan pulmonary circulation.10 Pulmonary endothelial dysfunction might lead to increased pulmonary vascular resistance and attenuation of the physiologic lowering of pulmonary vascular resistance induced by NO release.10
Administration of the selective pulmonary vasodilator inhaled NO to patients with Fontan circulation reduces pulmonary vascular resistance.10 However, NO has a high selectivity for the pulmonary circulation, with the potential disadvantage of increasing pulmonary capillary wedge pressure in patients with systemic ventricular dysfunction.11,12 Further, in a previous study, NO failed to increase cardiac output (CO) in Fontan patients.10 Sildenafil is a selective phosphodiesterase-5 (PDE-5) inhibitor, the predominant PDE isoform responsible for hydrolysis of cyclic guanosine-5'-monophosphate (GMP) (the second messenger of NO in vascular smooth muscle cells) in the lungs. Sildenafil has been shown to be as effective a pulmonary vasodilator as inhaled NO in patients with pulmonary arterial hypertension, and in children with congenital heart disease.10,13,14 Sildenafil also recently showed to be able to increase exercise capacity and pulmonary haemodynamics in pulmonary hypertension patients and in patients with acquired heart failure.15,16
The present randomized study sought to assess the short-term effects of sildenafil on cardiopulmonary function and on the haemodynamic response to exercise in Fontan patients.
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Methods |
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Study population
All Fontan patients >16 years old and currently followed-up at the Pediatric Cardiology and Adult Congenital Unit, University of Bologna, were candidates for inclusion in the study. Eligibility criteria for the study were: stability of clinical condition over the last 3 months and consent to participate in the study after information concerning procedures, risks, and possible clinical benefits. Exclusion criteria considered were severe heart failure (New York Heart Association functional class IV), presence of liver or renal dysfunction, transcutaneous arterial blood oxygen saturation (SaO2) <85% at rest, evidence of Fontan pathway obstruction, history of exercise-induced severe arrhythmias, and known or suspected pregnancy. Thirty-five patients were assessed for eligibility for the study (Figure 1). Five patients were excluded from the study because of non-compliance with the inclusion/exclusion criteria. Three patients refused to participate in the study. Twenty-seven eligible patients agreed to participate in the study. Data compiled for each patient included clinical and surgical history, physical examination, and exercise test results. All patients gave their written informed consent before participating in the study. The local ethics committee approved the study protocol. The present study complies with the Declaration of Helsinki.
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Study design
The study was planned as a prospective, randomized assessment of the acute effects of oral sildenafil on exercise capacity and haemodynamic response to exercise. The study protocol is illustrated in detail in Figure 1. Eligible patients were randomly assigned in a 2:1 fashion to sildenafil treatment or to no treatment. Allocation to the treatment or to the control group was done using minimization, considering the age (
22 vs. >22 years) and type of the Fontan (atrio-pulmonary vs. total cavo-pulmonary connection) as stratification variables.17 Patients who agreed to participate and fulfilled the inclusion criteria were progressively entered into MINIM computer software17 which provided information on the allocation of each patient to treatment or no treatment. Two different investigators were responsible for the randomization procedure and for the assignment to study group. All patients had performed a previous exercise test to become familiar with the procedure at an average of 11 ± 9 days before the study date (exercise test no. 1; Figure 2).On the day of the study, all patients underwent a baseline exercise test (exercise test no. 2). After having rested for 1 h, 18 patients allocated to treatment were given 0.7 mg/kg body weight sildenafil citrate orally (range 25–50 mg). These 18 patients repeated the exercise test (exercise test no. 3) 1 h after sildenafil administration, coinciding with the expected peak plasma concentration after oral loading. The remaining nine patients included in the control group received no treatment and repeated the exercise protocol after 2 h of rest. Both patients and investigators were not blinded to the results of the randomization procedure.
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Study endpoints and calculation of the sample size
The primary endpoint of the study was the change in peak VO2 from exercise test no. 2 to exercise test no. 3. For this endpoint, a non-inferiority test was conducted comparing sildenafil administration with no treatment. The null hypothesis was that the mean change in peak VO2 in the no treatment group equals that in the sildenafil group. Previous studies have shown that administration of a single dose of sildenafil to adults with left ventricular dysfunction increases peak VO2 by +8.9% on average,15 whereas the variability for peak VO2 for exercise tests performed at short distance is about +1%.18 With the assumption that the data were from approximately normal distributions with an SD of 5%, 24 patients randomized in a 2:1 fashion either to sildenafil or to no active treatment, respectively, provided 90% power to detect the above-mentioned difference with a two-sided 0.05 significance level. The number of patients randomized was extended to 27 to account for eventual drop-offs from the study.
Secondary endpoints of the study were the changes from exercise test no. 2 to exercise test no. 3 in rest and peak exercise CI, PBFi, and SaO2. Secondary endpoints were analysed using the all-randomized population.
Exercise test procedure
Exercise tests were performed with upright cycle ergometry (Ergoline, Germany), with the patient having fasted for at least 1 h. Oxygen uptake (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were measured with a computerized breath-by-breath analyzer (Innocor, Odense, Denmark). Patients performed a maximal exercise test using a 2 min incremental bicycle protocol with a work rate increment of 20 W every 2 min. Initial workload was 20 W. Criteria for test ending considered were patient exhaustion with a respiratory exchange ratio 
1.09. A 12-lead electrocardiogram and SaO2 were also continuously monitored throughout the study and cuff blood pressure was determined manually every 2 min. The technical details of measurement of peak VO2 and VE/VCO2 slopes were previously published.19 Resting HR was measured after at least 120 s in a seated position, and peak HR was defined as the maximal HR achieved during exercise. None of the patients were unable to exercise.
Haemodynamic measurements
The Innocor system was used to measure pulmonary blood flow (PBF) using a foreign gas rebreathing technique. The Innocor rebreathing system uses an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) and an inert insoluble gas (0.1% sulphur hexafluoride) from a 4 L pre-filled anaesthesia bag. Photoacustic analysers measure gas concentration over a 5-breath interval. During exercise, tidal volume was progressively increased in the closed circuit to match the physiologic increase. The use of sulphur hexafluoride allowed us to measure the volume of the lungs, valve, and rebreathing bag. Nitrous oxide concentration decreases during the rebreathing manoeuvre, with a rate proportional to PBF. Three to four respiratory cycles were needed to obtain nitrous oxide washout. Patients performed the exercise tests as described above, using a mouthpiece connected to the Innocor breathing system. Patients were instructed to signal approximately 1 min before peak exercise, to allow for measurement of peak exercise data. As previously reported, this technique is very reliable to measure effective PBF, both in children with the congenital heart disease and in adults with acquired heart failure.20–22 In all patients, blood haemoglobin concentration (g/dL) was assessed just before the first exercise test and was used in further analysis as reported. Before each test, all patients were exhaustively instructed on the breathing technique and performed at least two practice measurements before each test.
At baseline, three measurements of PBF were obtained at 3 min distance one from the other. During the measurement of PBF, all patients underwent a contemporaneous measurement of systolic and diastolic cuff blood pressure, of HR and of arterial SaO2. Further measurements of PBF were done in every patient at peak exercise. For all patients, the values of pulmonary vein saturations obtained in room air during the most recent cardiac catheterization were used in the analysis (average of 1.9 ± 1.4 years before the study). CO was measured using the formula: CO=1/[(arterial O2 content–venous O2 content)/VO2+1/PBF]. The values of PBF and CO obtained were indexed for body surface area to obtain PBF index and CI, respectively.
Inter-test assessment and adverse events
During the 60 min period before exercise test no. 3, patients were asked to rest in a supine position. Systolic and diastolic arterial blood pressures and SaO2 were measured every 15 min during this period. Patients in the treatment arm were asked to report any symptom occurring up to 12 h after sildenafil administration.
Statistical analysis
Continuous normally distributed variables are expressed as mean ± SD. Comparison of the percentage change in peak VO2, percentage change in rest and peak PBF index, CI, and SO2 observed from exercise test no. 2 to exercise test no. 3 in the sildenafil treatment group vs. the control group was made by Kruskal–Wallis test with Dunn’s post-test to correct for multiple comparisons. The Graphpad 4.03 statistical software was used for statistical analysis. A two-tailed probability value 0.05 was used as the criterion for statistical significance.
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Results |
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Twenty-seven patients (age 22.8 ± 4.9 years, range 16–32 years) were enrolled from February 2007 to August 2007. Eighteen patients received sildenafil treatment and nine patients received no treatment (Table 1). All patients completed the study protocol. No patient had additional forward flow to the pulmonary artery. Five patients in the treatment group and one patient in the control group had undergone previous pulmonary artery banding. All patients were free of complicating acute or chronic respiratory disease or other conditions that might affect exercise performance. Six patients in the sildenafil group and three patients in the control group had a SaO2 at rest >95%.
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Details on the cardiopulmonary and haemodynamic data observed in the treatment and control groups at rest and at each exercise stage are presented in Table 2.
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Cardiopulmonary exercise test results
All subjects exercised to the point of exhaustion. Patients receiving sildenafil had a higher improvement in peak VO2 (Figure 3) than control patients. SaO2 at rest and at peak exercise appeared to be similar in patients who received sildenafil and in the control group (Table 3). VE/VCO2 slope decreased by –6.9 ± 3.2% in patients treated with sildenafil (from 35.8 ± 6.9 to 33.2 ± 6.1), whereas it increased by 0.2 ± 3.3% in the control group (from 35.4 ± 7.3 to 35.4.2 ± 6.9). Exercise duration increased by 4.1 ± 3.2% and by 1.8 ± 2.9% in the sildenafil and control groups, respectively.
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Haemodynamic response to exercise
Details on the changes in haemodynamic variables observed in treatment group vs. the control group from exercise test no. 2 to exercise test no. 3 are shown in Table 3. Patients receiving sildenafil showed a higher increase in rest and peak exercise CI and PBFi when compared with the control group patients. No difference in the response of HR to exercise was observed in the two groups.
Inter-test assessment and adverse events
During the 60 min observation period before exercise test no. 3, we observed a progressive reduction in systolic and diastolic arterial blood pressures and an increase in SaO2 in the sildenafil treatment group, whereas no change was observed in the control group (data not shown). All patients tolerated sildenafil well; specifically, there was no symptomatic hypotension, facial flushing, or vision changes. However, one female patient reported mild headache that spontaneously resolved within 2 h from sildenafil administration.
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Discussion |
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The present study demonstrates that, in Fontan patients, the administration of a single oral dose of the PDE-5 inhibitor sildenafil might acutely improve exercise capacity and increase PBF and CI, both at rest and during exercise conditions.
Effect of sildenafil on Fontan haemodynamics
Although the Fontan operation has contributed greatly to the improvement of mortality rate in patients with a single ventricle,1,2 recent studies have emphasized a continuing risk of late failure and poor functional outcome in some long-term survivors.3,4 Decreased exercise tolerance and abnormal haemodynamic response to stress have also been clearly recognized in patients after this procedure.5,6 These results strongly suggest fundamental limitations inherent in Fontan physiology,7 related to increased afterload8 and reduced ventricular filling capacity with subsequently limited preload reserve,8,9 especially during conditions associated with increased HR.
Fontan patients, as patients with heart failure due to different aetiologies, have an abnormal systemic vascular tone, which may contribute to diminish skeletal muscle perfusion and heightened systemic vascular tone.10,23,24 Fontan patients also have an abnormal endothelium-dependent flow-mediated brachial artery dilation, which contributes to a reduced CO and to reduced exercise capacity.25 Sildenafil has previously been shown to improve endothelium-dependent flow-mediated brachial artery dilation in patients with heart failure,23,24 and to have systemic vasodilative properties as well.15 Lewis et al.15 demonstrated that oral administration of sildenafil is associated with a decrease in resting systemic vascular resistances and improved CI at rest and at peak exercise. Such an effect on systemic vascular resistances seems to be absent in normal subjects.26 Theoretically, sildenafil might have decreased ventricular afterload in Fontan patients in a similar way, acting as a systemic vasodilator, thus promoting increase in CI at rest and at peak exercise.
Another mechanism that might have contributed to explain the effect of sildenafil administration on CI and PBF index is an improvement in pulmonary haemodynamics. Evidence exists that a large proportion of the improvement in rest and exercise CI observed in adults with left ventricular systolic dysfunction after sildenafil administration is related to a decrease in pulmonary vascular resistances.15 The reason for this response lies in the presence of pulmonary endothelial dysfunction with increased pulmonary vascular resistance.15 Similarly, there is increasing evidence that up to 47% of Fontan patients may have increased pulmonary vascular resistance after a Fontan operation, as a consequence of pulmonary endothelial dysfunction.10 The mechanisms of pulmonary endothelial dysfunction in Fontan patients are only partially known, but the role of the loss of flow pulsatility appears to be important.10 Indeed, pulsatile flow is important for maintaining a low resistance in the pulmonary vasculature by passive recruitment of capillaries and shear-stress-mediated release of NO.10 Pulsatile flow has also been shown to be a more potent stimulus for release of NO to the same volume of laminar flow.27 Pulsatile shear stress acts on the endothelium via diverse mechanisms.28 Experimentally, induction of hyperpolarization of endothelial cell causes elevation of cyclic GMP via an NO-dependent mechanism, redistribution of the endothelial cytoskeletal protein (actin), and up-regulation of NO synthase gene transcription, which may be caused by pulsatile shear stress. Thus, reduced pulsatile shear stress in the Fontan pulmonary circulation may down-regulate the endothelial NO synthase expression and attenuate endothelial-dependent vasodilatation. This endothelial dysfunction seems to be reverted by inhaled NO.10 Given these hypotheses, the improvement in PBF index observed both at rest and during exercise after sildenafil administration could potentially be the result of decreased pulmonary vascular resistance induced by sildenafil through augmentation of cyclic GMP. In a recent contribution focusing on adults with left ventricular dysfunction, Lewis et al.15 have shown that the improvement in peak VO2 and peak CI following sildenafil administration was not uniform across the study cohort and was significantly higher in patients with pulmonary hypertension than in patients without. This finding could potentially hold true also for Fontan patients and could potentially explain the non-uniform response to sildenafil observed in the present study. It is conceivable that, even in the present study, Fontan patients with increased pulmonary resistances might have received the greatest benefit from sildenafil administration. The value of baseline pulmonary vascular resistance was not available in all subjects in the present study. Further research is needed to clarify the mechanisms by which sildenafil improves PBF index and CI in Fontan patients and the role of pulmonary vascular resistances in response to sildenafil.
Given the peculiarity of Fontan physiology, consisting in the presence of systemic and pulmonary artery resistances in series, both a decrease in systemic or pulmonary vascular resistance would be beneficial.
Effect of sildenafil on exercise capacity
As previously reported in other settings,15,16 we observed that sildenafil was associated with an improved peak exercise capacity. Such an improvement in peak exercise capacity is not present in healthy adults who do not have heart failure or pulmonary hypertension.26 The improvement in exercise capacity observed after sildenafil treatment may be attributed to several mechanisms. First, sildenafil might have improved exercise capacity by increasing CI during exercise. Furthermore, sildenafil might have improved skeletal muscle perfusion by increasing flow-mediated arterial vasodilatation.29 This might have corrected the non-uniform skeletal muscle unit perfusion that predisposes Fontan patients,25 as well other heart failure populations,24 to early anaerobic metabolism during exercise. Improvement in blood perfusion to exercising muscle might also have contributed by reducing the inappropriate ventilatory drive that is usually observed during exercise.
Safety of sildenafil
No major reactions to sildenafil occurred during the study period or during the following 12 h, supporting the good tolerability profile previously reported in arterial pulmonary hypertension.16 However, one female patient reported mild headache that spontaneously resolved within 2 h from sildenafil administration.
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Limitations |
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The present study has some limitations. First, patients were aware of receiving treatment or not. Therefore, we cannot exclude that the patient expectations might have lead to a higher level of effort during test no. 3 than during test no. 2. This could potentially lead to increased peak VO2, and peak exercise PBF and CI. However, we observed that individual peak respiratory quotient and peak HR values appeared to be similar in the two tests. Furthermore, increased effort would not explain the increase in PBF and CI observed at rest. Second, study subjects underwent two exercise tests on the same day. Hence, we are unable to determine whether antecedent exercise might have caused a different haemodynamic or gas exchange response to exercise during test no. 3 in the sildenafil vs. control group. Third, even though the increase in peak VO2 appeared statistically significant, the clinical relevance to patients receiving the treatment is yet to be demonstrated. Furthermore, it is currently unknown if the benefit in terms of exercise capacity observed acutely might persist during chronic treatment.
Conflict of interest: none declared.
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References |
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- Gentles TL, Mayer JE Jr, Gauvreau K, Newburger JW, Lock JE, Kupferschmid JP, Burnett J, Jonas RA, Castaneda AR, Wernovsky G. Fontan operation in five hundred consecutive patients: factors influencing early and late outcome. J Thorac Cardiovasc Surg (1997) 114:376–391.
[Abstract/Free Full Text] - Cetta F, Feldt RH, O’Leary PW, Mair DD, Warnes CA, Driscoll DJ, Hagler DJ, Porter CJ, Offord KP, Schaff HV, Puga FJ, Danielson GK. Improved early morbidity and mortality after Fontan operation: the Mayo Clinic experience, 1987 to 1992. J Am Coll Cardiol (1996) 28:480–486.[Abstract]
- Driscoll DJ, Offord KP, Feldt RH, Schaff HV, Puga FJ, Danielson GK. Five- to fifteen-year follow-up after Fontan operation. Circulation (1992) 85:469–496.
[Abstract/Free Full Text] - Gentles TL, Gauvreau K, Mayer JE Jr, Fishberger SB, Burnett J, Colan SD, Newburger JW, Wernovsky G. Functional outcome after the Fontan operation: factors influencing late morbidity. [Discussion 404–405]. J Thorac Cardiovasc Surg (1997) 114:392–403.
[Abstract/Free Full Text] - Rosenthal M, Bush A, Deanfield J, Redington A. Comparison of cardiopulmonary adaptation during exercise in children after the atriopulmonary and total cavopulmonary connection Fontan procedures. Circulation (1995) 91:372–378.
[Abstract/Free Full Text] - Gewillig M, Daenen W, Aubert A, Van der Hauwaert L. Abolishment of chronic volume overload. Implications for diastolic function of the systemic ventricle immediately after Fontan repair. Circulation (1992) 86(Suppl. 5):II93–II99.[Medline]
- Senzaki H, Masutani S, Kobayashi J, Kobayashi T, Sasaki N, Asano H, Kyo S, Yokote Y, Ishizawa A. Ventricular afterload and ventricular work in Fontan circulation: comparison with normal two-ventricle circulation and single-ventricle circulation with blalock-taussig shunts. Circulation (2002) 105:2885–2892.
[Abstract/Free Full Text] - Senzaki H, Masutani S, Ishido H, Taketazu M, Kobayashi T, Sasaki N, Asano H, Katogi T, Kyo S, Yokote Y. Cardiac rest and reserve function in patients with Fontan circulation. J Am Coll Cardiol (2006) 47:2528–2535.
[Abstract/Free Full Text] - Redington AN. The physiology of the Fontan circulation. Prog Pediatric Cardiol (2006) 22:179–186.[CrossRef]
- Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation (2003) 107:3204–3208.
[Abstract/Free Full Text] - Semigran MJ, Cockrill BA, Kacmarek R, Thompson BT, Zapol WM, Dec GW, Fifer MA. Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol (1994) 24:982–988.[Abstract]
- Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation (1994) 90:2780–2785.
[Abstract/Free Full Text] - Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation (2002) 105:2398–2403.
[Abstract/Free Full Text] - Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW, Zapol WM, Bloch KD, Semigran MJ. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol (2002) 90:677–680.[CrossRef][Web of Science][Medline]
- Lewis GD, Lachmann J, Camuso J, Lepore JJ, Shin J, Martinovic ME, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation (2007) 115:59–66.
[Abstract/Free Full Text] - Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med (2005) 353:2148–2157.
[Abstract/Free Full Text] - Altman DG, Bland JM. Treatment allocation by minimization. BMJ (2005) 330:843.
[Free Full Text] - Lehmann G, Kolling K. Reproducibility of cardiopulmonary exercise parameters in patients with valvular heart disease. Chest (1996) 110:685–692.[CrossRef][Web of Science][Medline]
- Giardini A, Specchia S, Coutsoumbas G, Donti A, Formigari R, Fattori R, Oppido G, Gargiulo G, Picchio FM. Impact of pulmonary regurgitation and right ventricular dysfunction on oxygen uptake recovery kinetics in repaired tetralogy of Fallot. Eur J Heart Fail (2006) 8:736–743.
[Abstract/Free Full Text] - Lang CC, Karlin P, Haythe J, Tsao L, Mancini DM. Ease of noninvasive measurement of cardiac output coupled with peak VO2 determination at rest and during exercise in patients with heart failure. Am J Cardiol (2007) 99:404–405.[CrossRef][Web of Science][Medline]
- Gabrielsen A, Videbaek R, Schou M, Damgaard M, Kastrup J, Norsk P. Non-invasive measurement of cardiac output in heart failure patients using a new foreign gas rebreathing technique. Clin Sci (Lond) (2002) 102:247–252.[Medline]
- Agostoni P, Cattadori G, Apostolo A, Contini M, Palermo P, Marenzi G, Wasserman K. Noninvasive measurement of cardiac output during exercise by inert gas rebreathing technique: a new tool for heart failure evaluation. J Am Coll Cardiol (2005) 46:1779–1781.
[Free Full Text] - Guazzi M, Tumminello G, Di Marco F, Guazzi MD. Influences of sildenafil on lung function and hemodynamics in patients with chronic heart failure. Clin Pharmacol Ther (2004) 76:371–378.[CrossRef][Web of Science][Medline]
- Koike A, Wasserman K, Taniguchi K, Hiroe M, Marumo F. Critical capillary oxygen partial pressure and lactate threshold in patients with cardiovascular disease. J Am Coll Cardiol (1994) 23:1644–1650.[Abstract]
- Inai K, Saita Y, Takeda S, Nakazawa M, Kimura H. Skeletal muscle hemodynamics and endothelial function in patients after Fontan operation. Am J Cardiol (2004) 93:792–797.[CrossRef][Web of Science][Medline]
- Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol (2004) 44:2339–2348.
[Abstract/Free Full Text] - Raj JU, Kaapa P, Anderson J. Effect of pulsatile flow on microvascular resistance in adult rabbit lungs. J Appl Physiol (1992) 72:73–81.
[Abstract/Free Full Text] - Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors. J Vasc Res (1998) 35:73–84.[CrossRef][Web of Science][Medline]
- Guazzi M, Casali M, Berti F, Rossoni G, Gennaro Colonna V, Guazzi M. Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients. Clin Pharmacol Ther (2007) Epub ahead of print.
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  A. Hager, S. Fratz, and J. Hess Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients Eur. Heart J., February 2, 2009; 30(4): 507 - 508. [Full Text] [PDF]
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A. Giardini Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients: reply Eur. Heart J., February 2, 2009; 30(4): 508 - 508. [Full Text] [PDF]
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