doi: 10.1161/CIRCHEARTFAILURE.108.796789
Original Articles |
PDE5A Inhibitor Treatment of Persistent Pulmonary Hypertension After Mechanical Circulatory Support
From the Divisions of Cardiology and Pulmonary and Critical Care Medicine, Department of Medicine (R.J.T., A.R.H., S.D.R., I.S.W., M.M., A.L.Z., S.C.M., D.R.T., P.M.H., R.E.G., J.B.O., H.C.C.); and Division of Cardiac Surgery, Department of Surgery (A.S.S., D.Y., J.V.C.), The Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Hunter C. Champion, MD, PhD, Division of Cardiology, Department of Medicine, Johns Hopkins University, 720 Rutland Avenue, Ross 835, Baltimore, MD 21205. E-mail hcc{at}jhmi.edu
Received January 7, 2008; accepted September 25, 2008.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods and ResultsResultsDiscussionReferences |
|---|
Background— Pulmonary hypertension (PH) secondary to left heart failure portends a poor prognosis and is a relative contraindication to heart transplantation at many centers. We tested the hypothesis that when PH persists after adequate left ventricle unloading via recent left ventricular assist device (LVAD) therapy, phosphodiesterase type 5A inhibition would decrease PH in this population.
Methods and Results— We performed an open-label clinical trial using control patients not receiving therapy. Between 1999 and 2007, 138 consecutive patients undergoing cardiac transplantation evaluation with advanced left ventricular dysfunction, an elevated pulmonary capillary wedge pressure, and PH (defined by a pulmonary vascular resistance (PVR) >3 Woods Units), were treated with LVAD therapy. Fifty-eight of these patients reduced their pulmonary capillary wedge pressure to a value <15 mm Hg (11.8±2.0 mm Hg from baseline 23.2±6.2 mm Hg) 1 to 2 weeks after LVAD implantation, but despite this improvement, the PVR of these patients was only minimally affected (5.65±3.00 to 5.39±1.78 Wood Units). Twenty-six consecutive patients from this group with persistently elevated PVR were started on oral phosphodiesterase type 5A inhibition with sildenafil and titrated to an average of dose of 51.9 mg by mouth 3 times per day. The average PVR in the sildenafil-treated group fell from 5.87±1.93 to 2.96±0.92 Wood Units (P<0.001) and the mean pulmonary artery pressure fell from 36.5±8.6 to 24.3±3.6 mm Hg (P<0.0001) and was significantly lower when compared with the 32 LVAD recipients not receiving sildenafil at weeks 12 to 15 after the initial post-LVAD hemodynamic measurements (13 to 17 weeks post-LVAD implantation). In addition, hemodynamic measurements of right ventricular function in sildenafil-treated patients was also improved compared with patients not receiving sildenafil.
Conclusions— In patients with persistent PH after recent LVAD placement, phosphodiesterase type 5A inhibition in this open-label trial resulted in a significant decrease in PVR when compared with control patients.
Key Words: heart failure • PDE5A inhibition • sildenafil • hypertension, pulmonary • transplantation
|
Introduction |
|---|
|
TopAbstractIntroductionMethods and ResultsResultsDiscussionReferences |
|---|
Heart transplantation is a recognized treatment for end-stage heart disease. To ensure the best allocation of this scarce resource, significant risk factors for death after transplantation have been identified including an elevated pulmonary vascular resistance (PVR)
3 Wood Units.1 The International Society for Heart and Lung Transplantation database of 55 359 patients showed a linear relationship between PVR and transplant mortality.2 Therefore, pulmonary hypertension (PH), measured as increased PVR, has become not only a risk factor for mortality, but a relative contraindication to cardiac transplantation.
Editorial p 211
PH from associated left-sided heart failure is thought to result from both a reactive increase in vascular smooth muscle tone as well as a relatively fixed structural remodeling.3 The former has been shown to be acutely reversible with vasodilators including nitroprusside,4,5 milrinone,6 dobutamine,7 prostaglandin E1,7,8 prostacyclin analogs,9,10 and inhaled nitric oxide (NO).11,12 The ability to respond to an acute vasodilator challenge has been shown to differentiate groups at high risk of perioperative mortality (those with persistently elevated, "fixed" PVR) from lower risk, transplantable groups.4,13,14 Two small studies have suggested that sildenafil may be useful as a method to test for acute vasodilatory reversibility in heart failure patients.15,16 Lewis et al17 recently demonstrated that a single dose of sildenafil reduced pulmonary artery pressure (PAP) and PVR in patients with PH secondary to New York Heart Association class III heart failure as well as improved peak V02 and exercise performance.
Pulmonary vascular remodeling observed in patients with PH from left-sided heart failure leading to what has been sometimes termed "fixed" or persistent PH and may include medial hypertrophy with or without intimal fibrosis, but a noted absence of plexiform lesions (which are observed in primary PH).18,19 These structural changes and lack of acute reversibility may not represent an irreversible abnormality as 80% of patients who underwent a cardiac transplantation despite persistent PH normalized their PVR by 1 year.20 The precise time course for reversal is unknown, as a more recent study suggests that PVR can normalize as early as 30 days after transplantation.21 Although the pulmonary vascular remodeling may slowly revert once blood flow has normalized, cardiac transplantation in the setting of an elevated PVR increases the risk of acute right ventricular (RV) failure in the perioperative period.
Several strategies, described in case reports, have attempted to reverse the persistent component of PH to obtain a transplantable PVR value in patients not responsive to acute vasodilatory challenge including long-term prostacyclin administration,14 cardiac resynchronization therapy,22 long-term inotropic therapy so-called "vasodilator conditioning" with milrinone or dobutamine,23 and nesiritide.24 In addition, small studies report a decrease PVR in persistent PH to a transplantable level after implantation of a left ventricular assist device (LVAD).25–28 Importantly, this reversal occurred over 6 weeks to 1 year.27,28
In an attempt to augment this process, oral phosphodiesterase type 5A (PDE5A) inhibitor, sildenafil, appeared as a good candidate. In dogs, long-term oral PDE5A inhibitors significantly inhibited the development of PH secondary to heart failure.29 Furthermore, Jabbour et al recently published a case series of 6 patients with a cardiomyopathy, an elevated pulmonary capillary wedge pressure (PCWP; average 26.3 mm Hg), and an elevated PVR who were treated with sildenafil to allow for transplantation. In most of these patients, a decrease in PVR and transpulmonary gradient was observed and transplantation was performed.30 Several case reports exist in which long-term oral sildenafil therapy decreased PVR in a patient with an elevated PCWP to a transplantable level.31,32
Given its pharmacological properties and success in patients with other clinical profiles, we performed an open-label clinical trial of sildenafil in LVAD recipients and compared them with historical controls. We hypothesized that PDE5A inhibition will decrease PVR when PH persists despite adequate left ventricle unloading.
|
Methods and Results |
|---|
|
TopAbstractIntroductionMethods and ResultsResultsDiscussionReferences |
|---|
Patients
A research protocol designed to determine the effects of sildenafil on PAP and PVR was approved by the Johns Hopkins University Institutional Review Board for the open-label use of human subjects. Twenty-six consecutive patients with advanced left ventricular dysfunction, treatment with LVAD implantation, and persistent PH (defined by a PVR>3 Wood Units 7 to 14 days after LVAD implantation) despite normalization of their PCWP to a value <15 mm Hg were consented for and received treatment with sildenafil in an attempt to reduce PVR before cardiac transplantation. Patients with the combined use of LVADs and RVADS were not used. Patients receiving chronic inotrope therapy were excluded from this study. No patients received placebo. Patients in the sildenafil treatment group did not have their angiotensin converting enzyme inhibitor/angiotensin receptor blocker, hydralazine, or β-blocker therapy increased after initiation of sildenafil treatment.
For comparison with the sildenafil-treated patients, we reviewed and included all 138 consecutive patients who received LVAD implantation from 1999 to 2007 at our institution. From this group, a total of 58 patients had persistently elevated PVR at the time of subsequent right heart catheterization performed 7 to 14 days post-LVAD implantation of which 26 received sildenafil and 32 did not receive sildenafil. No patients refused sildenafil therapy.
Hemodynamic Measurements
All patients underwent routine right heart catheterization 7 to 14 days (average time, 9.7 days) after the implantation of their LVAD to determine the presence or absence of PVR3 Woods Units and repeated serially at 1- to 3-month intervals after the institution of sildenafil treatment. Patients received no medications by mouth on the morning of subsequent right heart catheterizations. Right heart catheterization was performed as described previously.6 Cardiac output was determined by thermodilution. Right heart catheterization pressure waveforms data were additionally analyzed for augmentation index (PA 
P/PP), contractility index (dP/dtmax/IP), and isovolumic relaxation time constant (
, ms) to determine parameters of pulmonary arterial stiffness, RV systolic function, and RV diastolic function, respectively. This analysis was performed using custom software (WinPVAN, version 3.5.8). Transthoracic echocardiograms were conducted on all patients after right heart catherization to measure tricuspid annular plane systolic excursion (an echocardiographic surrogate of RV systolic function).
Sildenafil Treatment
Patients meeting the above inclusion criteria were started on sildenafil at a dose of 25 mg by mouth 3 times per day with a target dose of 75 mg 3 times a day. The dose was advanced every 2 to 4 days based on tolerability (symptomatic hypotension, gastric reflux, headache, facial flushing) to a final average dose of 51.9±4.4 mg. All patients tolerated some dose of the medication, and the final dose was achieved in 5 to 7 days. After this initial dose titration, there was no further alteration.
Statistical Analysis
The data are presented as the mean±SD. A statistical software package (Prism, version 5.01 for Windows; Graphpad Software Inc) was used for the analysis. Continuous variables were compared using the Student t test (unpaired for between-group analyses). Proportions were compared using 
2. The primary end point of the 12 to 15 weeks change in PVR and dP/dtmax/IP was analyzed using an unpaired Student t test. All results were tested for 2-sided significance. A probability value <0.05 was considered to be criterion for statistical significance.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethods and ResultsResultsDiscussionReferences |
|---|
Twenty-six consecutive patients with advanced left ventricular dysfunction, treatment with LVAD implantation, and persistent PH (defined by a PVR>3 Wood Units 7 to 14 days after LVAD implantation) despite normalization of PCWP to a value <15 mm Hg were treated with sildenafil to lower PVR before cardiac transplantation. Thirty-two consecutive LVAD control subjects were identified as outlined above. Table 1 outlines the characteristics of these 2 groups including pre- and post-LVAD medication use. Baseline pre- and post-LVAD hemodynamic values are shown in Table 2 in both groups before open-label treatment with sildenafil. Both groups were similar with regard to pre- and post-LVAD hemodynamics. Figure 1 shows summary data including the influence of LVAD therapy on cardiac output, mean pulmonary arterial pressure, PCWP, and calculated PVR of the entire combined cohort. Despite normalization of PCWP and a significant increase in cardiac output, this cohort of patients had a change in PVR after intervention with LVAD (5.65±3.00 to 5.39±1.78 Wood Units) that was not statistically significant (P=0.56; Figure 1). The transpulmonary gradient increased significantly from 13.7±6.9 to 22.8±7.9 mm Hg (P<0.001).
|
|
|
In the 26 patients receiving sildenafil, there was a significant lowering of mean PAP from 36.5±8.6 to 24.3±3.6 mm Hg (P<0.0001; Figure 2) and PVR from 5.87±1.93 to 2.96±0.92 Wood Units (mm Hg L–1min–1; P<0.001; Figure 2) after 2 to 4 weeks of therapy. This improvement in PVR was maintained through 12 to 15 weeks after sildenafil initiation (Figure 3). In contrast, in LVAD control patients with similar baseline clinical (Table 1) and hemodynamic parameters, there was not a statistically significant reduction in PVR during the same time period (13 to 17 weeks post-LVAD implantation; P=0.074), although there was a trend toward significance.
|
|
In addition to improvements in PVR and transpulmonary gradient, patients treated with sildenafil showed marked improvement in RV systolic and diastolic function, as measured by RV contractility index (dP/dtmax/IP; 8.69±1.78 to 13.1±3.3; P<0.0001) and
(91.9±17.7 to 63.6±17.8 ms; P<0.0001), respectively (Figure 4). Pulmonary artery augmentation index was also decreased after sildenafil treatment from 0.195±0.04 to 0.126±0.02; P<0.0001) and tricuspid annular plane systolic excursion increased from 1.73±0.21 to 2.00±0.2 cm (P<0.001), suggesting a reduced large artery pulmonary vascular stiffness. The increase in RV dP/dtmax/IP in patients that received sildenafil at 2 to 4 weeks was sustained through 12 to 15 weeks.
|
Treatment with sildenafil did not elevate the PCWP or diminish cardiac output (Figure 2). Furthermore, sildenafil was well tolerated, and there was no increased incidence of arrhythmias (atrial fibrillation, ventricular tachycardia, and ventricular fibrillation) based on bimonthly interrogation of internal cardioverter defibrillators as well as Holter monitoring (data not shown). Four patients experienced facial flushing that occurred immediately after the first 2 doses. Two patients reported gastric reflux that began after the first administered dose and continued until day 3 of treatment with spontaneous resolution. None of these reported events resulted in the alteration of dose or discontinuation of drug therapy until after transplantation. After cardiac transplantation, patients were maintained on sildenafil until their first right heart catheterization, at which time patients’ dosing was tapered over the following week.
Of the 26 sildenafil-treated patients, 24 reduced their PVR to below 3 Wood Units, and 19 were deemed transplant eligible with the remainder being classified for destination LVAD therapy. Of this group 10 patients have been transplanted to date without surgical complication. One patient treated with sildenafil had postoperative RV dysfunction defined as either requirement of inhaled NO>48 hours or intravenous inotrope therapy for>72 hours posttransplant for RV dysfunction. Of the LVAD control patients, 18 were transplanted without surgical complication. Five of the 18 patients had RV dysfunction postoperatively (P=0.27).
|
Discussion |
|---|
|
TopAbstractIntroductionMethods and ResultsResultsDiscussionReferences |
|---|
End-stage heart failure is associated with significant mortality. Cardiac transplantation is the treatment of choice. PH as defined by an elevated PVR has consistently been identified as a risk for peritransplant mortality and is a relative contraindication to transplantation at most centers. Among potential cardiac transplant candidates with severe left ventricular systolic dysfunction and subsequent PH, there exists a subset of patients in which traditional vasodilators or LVAD therapy does not acutely lower PVR to a level <3 Wood Units. In our cohort of patients with persistent PH who failed to improve early after LVAD implantation, addition of PDE5A inhibition with sildenafil along with continued LVAD support substantially and rapidly lowered mean PAP and PVR to levels <3 Wood Units. Measurements of RV function also showed significant improvement after sildenafil treatment. There were no adverse reactions to the therapy.
Our cohort supports and extends the findings by Alaeddini et al,16 who showed that sildenafil acutely lowered PVR in ICU patients with left-sided cardiac failure, all of which were already on some type of inotrope or vasodilator therapy and had an elevated PCWP. With regard to its potential to allow for transplantation, it supports and extends to the case report by Gomez-Moreno et al,31 in which a dilated cardiomyopathy patient with a persistently elevate PVR (from Becker muscular dystrophy) failed dobutamine infusion and was treated with 4 months of sildenafil and later successfully transplanted after lowering PVR to a level considered acceptable for transplantation. Jabbour et al30 used sildenafil to lower PVR in potential cardiac transplant patients, although these patients had elevated PCWP and also demonstrated a response to nitrates or prostacyclins. Thus, the degree of persistent PH in these patients could not be quantified.
Our study suggests that sildenafil may lead to significant hemodynamic improvement in patients with PH from left heart failure unresponsive to LVAD therapy (despite normalization of the PCWP). After initiation of sildenafil, there was a marked reduction in PVR, allowing for potential transplantation at our center. Although previous studies have indicated the PVR will improve with LVAD therapy alone, the time period for improvement is relatively lengthy (6 weeks to 1 year).27,28 In our control LVAD patients, PVR began to trend lower by 12 to 15 weeks (13 to 17 weeks post-LVAD implantation) as seen in Figure 4; however, these patients still had an average PVR>4, a value not yet ideal for transplantation. The decrease in PVR was not statistically significant at this time point. Although previous findings suggest PVR values would continue to decline after persistent unloading of the left ventricle and return of normal pulmonary flow, the time frame to achieve this normalization may be prolonged. In our sildenafil cohort, PVR dropped to a transplantable level by 2 to 4 weeks, and this drop was maintained and sustainable with continued therapy over the next several months. It is possible that PVR was lowered even before this time period since Alaeddini et al witnessed a drop in as little as 4 hours. The ability to lower PVR in such a short time frame allows for the potential of earlier transplantation as well as improved hemodynamics in destination LVAD patients. In fact, Klodell et al33 recently reported using sildenafil to wean inotropic support and inhaled NO from 10 newly implanted LVAD patients.
In addition to its effect on PVR and PAP, sildenafil treatment combined with LVAD improved several measurements of RV function including RV dP/dtmax/IP and (Figure 4). Nagendran et al34 recently showed that PDE5A is upregulated in hypertrophied human RV and acute inhibition with sildenafil can improve contractility evidenced by an increase in RV dP/dtmax. Sildenafil has previously been shown to influence in animal models of heart failure.35 These findings may suggest that sildenafil can improve RV function through mechanisms other than simply lowering PVR and PAP. The relative contribution to hemodynamic improvement is yet to be elucidated. Sildenafil-treated patients witnessed an improvement in tricuspid annular plane systolic excursion, which has previously be shown to be of significant prognostic value.36 A decrease in pulmonary arterial stiffness measured by augmentation index was also observed.
PDE5A, the enzyme responsible for catabolism of cGMP in the lung, has previously been shown to be upregulated in animal models of hypoxia induced PH as well as in humans with pulmonary arterial hypertension.37,38 Because of the success in lowering PVR with sildenafil (a potent PDE5A inhibitor) in our cohort, it is likely that PDE5A plays an important role in this human disease process, specifically one component of persistent PH in left-sided heart failure. This could be the result of upregulation of PDE5A. Patients with persistent PH are unresponsive to inhaled NO in terms of vasodepressor response.11,12 cGMP is the second messenger of the NO vasodilatory cascade. If PDE5A is upregulated to the point where it can immediately catabolize any cGMP produced from the inhaled NO, this may explain the lack of vasodilatory response. If this is true in persistent PH in heart failure, then inhibition of the catabolism of cGMP may allow for pulmonary vasodilatation and subsequent lowering of PVR.
This study has its limitations that must be considered. It is an open-label trial, which uses controls that were not treated with sildenafil before those that received the PDE5A inhibitor. With this in mind, other changes in selection or therapies in addition to the sildenafil may have occurred during the more recent time period. Moreover, the actual timing of the initial PVR drop cannot be determined as the first measure of PVR after initiation of sildenafil therapy did not occur until 2 to 4 weeks. It is possible that other vasodilator therapies such as nesiritide or chronic nitrates may reduce mean PAP and PVR in LVAD patients with persistently elevated PVR. Six patients in our cohort were receiving nitrate/hydralazine combination for afterload reduction in the setting of angiotensin converting enzyme inhibitor/angiotensin receptor blocker intolerance. This group was on nitrate therapy before LVAD implantation as well as afterward. No patients received nesiritide.
Certainly further study is needed to define the role of chronic PDE5A inhibition in the setting of left ventricular dysfunction associated with persistent PH including randomized controlled trials with morbidity and mortality outcomes. Several important questions are yet to be answered, including the timing at which to initiate sildenafil therapy. If PDE5A is upregulated in this disease process, earlier treatment with PDE5A inhibitors might prevent the development of PH as seen in animal models.29 It is not yet known whether PDE5A inhibition should be started before LVAD therapy.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported in part by the Bernard A. and Rebecca S. Bernard Foundation, a scientist development grant from the American Heart Association, the W.W. Smith Foundation, and NIH P50 HL084946. Dr Champion is a Fellow of the American Heart Association and the Pulmonary Vascular Research Institute. He is a recipient of the Zipes Distinguished Young Investigator Award of the American College of Cardiology, the Shin Chun-Wang Young Investigator Award, and the Giles F. Filley Memorial Award from the American Physiological Society. Dr Thiemann is supported in part by the Donald W. Reynolds Foundation. Dr Girgis receives clinical research funding from Pfizer.
Disclosures
Dr Champion is a speaker for Pfizer related to pulmonary arterial hypertension (WHO category 1).
|
References |
|---|
|
TopAbstractIntroductionMethods and ResultsResultsDiscussionReferences |
|---|
1. McCarthy JF, McCarthy PM, Massad MG, Cook DJ, Smedira NG, Kasirajan V, Goormastic M, Hoercher K, Young JB. risk factors for death after heart transplantation: does a single-center experience correlate with multicenter registries? Ann Thorac Surg. 1998; 65: 1574–1578.
2. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The registry of the international society for heart and lung transplantation: seventeenth official report—2000. J Heart Lung Transplant. 2000; 19: 909–931.[CrossRef][Medline]
3. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000; 102: 1718–1723.
4. Zakliczynski M, Zebik T, Maruszewski M, Swierad M, Zembala M. Usefulness of pulmonary hypertension reversibility test with sodium nitroprusside in stratification of early death risk after orthotopic heart transplantation. Transplant Proc. 2005; 37: 1346–1348.[CrossRef][Medline]
5. Costard-Jackle A, Fowler MB. 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]
6. Givertz M, Michael M, Hare M, Joshua M, Loh M, Evan, Gauthier DF, Colucci MD, FACC, Wilson S. Effect of bolus milrinone on hemodynamic variables and pulmonary vascular resistance in patients with severe left ventricular dysfunction: a rapid test for reversibility of pulmonary hypertension. J Am Coll Cardiol. 1996; 28: 1775–1780.[Abstract]
7. Murali S, Uretsky BF, Reddy PS, Tokarczyk TR, Betschart AR. Reversibility of pulmonary hypertension in congestive heart failure patients evaluated for cardiac transplantation: comparative effects of various pharmacologic agents. Am Heart J. 1991; 122: 1375–1381.[CrossRef][Medline]
8. Radovancevic B, Vrtovec B, Thomas CD, Croitoru M, Myers TJ, Radovancevic R, Khan T, Massin EK, Frazier OH. Nitric oxide versus prostaglandin e1 for reduction of pulmonary hypertension in heart transplant candidates. J Heart Lung Transplant. 2005; 24: 690–695.[CrossRef][Medline]
9. Sablotzki A, Czeslick E, Gruenig E, Friedrich I, Schubert S, Borgermann J, Hentschel T. First experiences with the stable prostacyclin analog iloprost in the evaluation of heart transplant candidates with increased pulmonary vascular resistance. J Thorac Cardiovasc Surg. 2003; 125: 960–962.
10. Weston MW, Isaac BF, Crain C. The use of inhaled prostacyclin in nitroprusside-resistant pulmonary artery hypertension. J Heart Lung Transplant. 2001; 20: 1340–1344.[CrossRef][Medline]
11. Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, Kaine SF, Ivy DD, Webber SA, Rothman A, Ross RD, Aggarwal S, Takahashi M, Waldman JD. Inhaled nitric oxide as a preoperative test (INOP test I): the INOP Test Study Group. Circulation. 2002; 106: 76I–I81.
12. Fojon S, Fernandez-Gonzalez C, Sanchez-Andrade J, Lopez-Perez JM, Hermida LF, RodrI'guez JA, Juffe A. Inhaled nitric oxide through a noninvasive ventilation device to assess reversibility of pulmonary hypertension in selecting recipients for heart transplant. Transplant Proc. 2005; 37: 4028–4030.[CrossRef][Medline]
13. Chen JM, Levin HR, Michler RE, Prusmack CJ, Rose EA, Aaronson KD. 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.
14. Klotz S, Deng MC, Hanafy D, Schmid C, Stypmann J, Schmidt C, Hammel D, Scheld HH. Reversible pulmonary hypertension in heart transplant candidates—pretransplant evaluation and outcome after orthotopic heart transplantation. Eur J Heart Fail. 2003; 5: 645–653.
15. Angel Gomez-Sanchez M, Saenz de la Calzada C, Escribano Subias P, Francisco Delgado Jimenez J, Lazaro Salvador M, Albarran Gonzalez A, Cea Calvo L. Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation. Eur J Heart Fail. 2004; 6: 615–617.[CrossRef][Medline]
16. Alaeddini J, Uber PA, Park MH, Scott RL, Ventura HO, Mehra MR. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am J Cardiol. 2004; 94: 1475–1477.[CrossRef][Medline]
17. 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.
18. Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, Pa: Elsevier Saunders; 2005.
19. Delgado JF, Conde E, Sanchez V, Lopez-Rios F, Gomez-Sanchez MA, Escribano P, Sotelo T, Gomez de la Camara A, Cortina J, de la Calzada CS. Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure. Eur J Heart Fail. 2005; 7: 1011–1016.
20. Bhatia SJ, Kirshenbaum JM, Shemin RJ, Cohn LH, Collins JJ, Di Sesa VJ, Young PJ, Mudge GHJ, Sutton MG. Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation. Circulation. 1987; 76: 819–826.
21. Delgado JF, Gomez-Sanchez MA, Saenz de la Calzada C, Sanchez V, Escribano P, Hernandez-Afonso J, Tello R, Gomez de la Camara A, Rodriguez E, Rufilanchas JJ. Impact of mild pulmonary hypertension on mortality and pulmonary artery pressure profile after heart transplantation. J Heart Lung Transplant. 2001; 20: 942–948.[CrossRef][Medline]
22. Healey JS, Davies RA, Tang ASL. Improvement of apparently fixed pulmonary hypertension with cardiac resynchronization therapy. J Heart Lung Transplant. 2004; 23: 650–652.[CrossRef][Medline]
23. Stobierska-Dzierzek B, Awad H, Michler RE. The evolving management of acute right-sided heart failure in cardiac transplant recipients. J Am Coll Cardiol. 2001; 38: 923–931.
24. Bhat G, Costea A. Reversibility of medically unresponsive pulmonary hypertension with nesiritide in a cardiac transplant recipient. ASAIO J. 2003; 49: 608–610.[CrossRef][Medline]
25. Haddad H, Elabbassi W, Moustafa S, Davies R, Mesana T, Hendry P, Masters R, Mussivand T. Left ventricular assist devices as bridge to heart transplantation in congestive heart failure with pulmonary hypertension. ASAIO J. 2005; 51: 456–460.[CrossRef][Medline]
26. Choong CK, Pasque MK, Shelton K, Kehoe-Huck B, Ewald GA, Horstmanshof D, Moazami N. The beneficial role of left ventricular assist device destination therapy in the reversal of contraindications to cardiac transplantation. J Thorac Cardiovasc Surg. 2005; 130: 879–880.
27. Salzberg SP, Lachat ML, von Harbou K, Zund G, Turina MI. Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates. Eur J Cardiothorac Surg. 2005; 27: 222–225.
28. Martin J, Siegenthaler MP, Friesewinkel O, Fader T, van de Loo A, Trummer G, Berchtold-Herz M, Beyersdorf F. Implantable left ventricular assist device for treatment of pulmonary hypertension in candidates for orthotopic heart transplantation—a preliminary study. Eur J Cardiothorac Surg. 2004; 25: 971–977.
29. Yamamoto T, Wada A, Tsutamoto T, Ohnishi M, Horie M. Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway. J Cardiovasc Pharmacol. 2004; 44: 596–600.[CrossRef][Medline]
30. Jabbour A, Keogh A, Hayward C, Macdonald P. Chronic sildenafil lowers transpulmonary gradient and improves cardiac output allowing successful heart transplantation. Eur J Heart Fail. 2007; 9: 674–677.
31. Gomez-Moreno S, Lage E, Hernandez A, Campos A, Cabezon S, Ordonez A, Hinojosa R. Use of oral sildenafil in patients with irreversible pulmonary hypertension not eligible for heart transplantation. Transplant Proc. 2005; 37: 1550–1551.[CrossRef][Medline]
32. Mogollón MV, Lage E, Cabezón S, Hinojosa R, Ballesteros S, Aranda A, Sobrino JM, Ordóñez A. Combination therapy with sildenafil and bosentan reverts severe pulmonary hypertension and allows heart transplantation: case report. Transplant Proc. 2006; 38: 2522–2523.[CrossRef][Medline]
33. Klodell J, Charles T, Morey TE, Lobato EB, Aranda J, Juan M, Staples ED, Schofield RS, Hess PJ, Martin TD, Beaver TM. Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices. Ann Thorac Surg. 2007; 83: 68–71.
34. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St. Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JRB, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007; 116: 238–248.
35. Takimoto E, Champion H, Li M, Belardi D, Ren S, Rodriguez E, Bedja D, Gabrielson K, Wang Y, Kass D. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005; 11: 214–222.[CrossRef][Medline]
36. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006; 174: 1034–1041.
37. Jernigan NL, Resta TC. Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation. Am J Physiol Lung Cell Mol Physiol. 2002; 282: L1366–L1375.
38. Hemnes AR, Mahmud M, Wigley F, Rodriguez ER, Girgis RE, Yang SC, Conte JV, Orens JB, Champion HC. Pulmonary hypertension is associated with increased expression and activity of phosphodiesterase type 5A (PDE5A). Presented as abstract at the AHA Scientific Sessions, Dallas, Tex, 2005.
This article has been cited by other articles:
 |
|
 |
|
  M. J. Semigran Phosphodiesterase Type 5 Inhibition: A Support of the Left Ventricular Assist Device Bridge to Transplant Circ Heart Fail, November 1, 2008; 1(4): 211 - 212. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||