Ann Thorac Surg 2006;82:1770-1773
© 2006 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Reversible Pulmonary Hypertension in Heart Transplant Candidates: To Transplant or Not to Transplant
Stefan Klotz, MDa,*,
Frauke Wenzelburger, MDa,
Joerg Stypmann, MDb,
Henryk Welp, MDa,
Gabriele Drees, MDa,
Christof Schmid, MDa,
Hans H. Scheld, MDa
a Department of Thoracic and Cardiovascular Surgery, University Hospital Muenster, Muenster, Germany
b Department of Cardiology and Angiology, University Hospital Muenster, Muenster, Germany
Accepted for publication May 25, 2006.
* Address correspondence to Dr Klotz, Department of Thoracic- and Cardiovascular Surgery, University Hospital Münster, Albert-Schweitzer-Str. 33, 48149 Münster, Germany (Email: stefan.klotz{at}ukmuenster.de).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, Jan 30–Feb 1, 2006.
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Abstract
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BACKGROUND: Pulmonary hypertension (PHT), defined as a pulmonary vascular resistance (PVR) greater than 2.5 Wood units [WU] and(or) transpulmonary gradient (TPG) greater than 12 mm Hg, is a risk factor for mortality in cardiac transplantation due to elevated postoperative right heart failure. Orthotopic heart transplantation is possible if PVR could be reversed below 2.5 WU and TPG below 12 mm Hg. We show the Muenster experience from the last 10 years.
METHODS: From April 1996 to December 2005 all cardiac transplant recipients separated into patients with and without PHT were included. All patients with PHT had successful reduction (PVR 
2.5 WU and TPG 12 mm Hg) using prostaglandin I2 or E1. Posttransplant early and late mortality and incidence of right heart failure were studied.
RESULTS: Two hundred seventeen patients were included in this study. Of these, 168 had normal pulmonary pressures (non-PHT group), 49 (22.6%) had reversible PHT (rev-PHT group). Mean PVR was 1.6 ± 1.1 WU vs 2.1 ± 1.1 WU (p < 0.01; non-PHT vs rev-PHT) and mean TPG 8.0 ± 1.9 mm Hg vs 10.6 ± 4.1 mm Hg (p = not significant [NS]). Thirty-day survival after orthotopic cardiac transplantation was 85% vs 78% (p = 0.150) and 10 year survival 63% vs 61% (p = NS). Right heart failure during the first 30 days after transplantation occurred in 27% in the non-PHT group and in 64% in the rev-PHT group (p = 0.035). However, in patients transplanted after 2001 it did not appear.
CONCLUSIONS: Cardiac transplant candidates with reversible PHT have still significantly elevated pulmonary pressures compared with patients without PHT. Despite a significantly higher risk of right heart failure, long-term survival after orthotopic cardiac transplantation was not affected.
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Introduction
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Heart transplantation is the most effective treatment for well-selected patients with endstage heart-failure. Several studies have confirmed that elevated pulmonary vascular resistance (PVR) or transpulmonary gradient (TPG) is a risk factor for mortality in the early and late courses after orthotopic heart transplantation, due to the high risk of right ventricular failure, because the grafted heart is unable to adapt to significant pulmonary hypertension (PHT) in the immediate postoperative period [1–5]. Although the degree of PHT that is an absolute contraindication for orthotopic transplantation is unknown, many institutions transfer only patients to the waiting list if the PVR is lower than 2.5 Wood units (WU) and the TPG lower than 12 mm Hg [6, 7]. However, an international consensus about these values is not available. In the preoperative evaluation of patients, it is extremely important to determine whether or not PHT can be reversed. Several pharmacologic agents have been used in the assessment of reversibility of PHT including nitroprusside, nitric oxide, milrinone, prostaglandin E1, and I2 [1, 5, 8–12]. We have recently shown that especially prostaglandin E1 is very effective in lowering PHT [13]. The studies regarding the long-term outcome in this patient group are nonuniform. Recently, Butler and colleagues [14] presented a study with increased mortality in patients with reversible PHT during a follow-up of 42 months. Our study was undertaken to evaluate the Muenster experience of cardiac transplant patients with reversible PHT and their short-term and long-term outcome after orthotopic transplantation compared with patients without PHT.
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Patients and Methods
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Two hundred seventeen consecutive heart-transplant candidates from our Interdisciplinary Heart Failure and Transplant Program at Muenster University Hospital [15] above the age of 17 years were retrospectively analyzed for PHT at the time of pretransplant evaluation. All cardiac transplantations were performed orthotopic or total orthotopic as described by Shumway and Stinson [16]. Patients with implanted mechanical assist devices at the time of cardiac transplantation were excluded from this study.
All patients underwent right heart catheter for hemodynamic evaluation between April 1996 and December 2005. Catheterization was performed with a Swan Ganz catheter (Baxter Healthcare Corp, Irvine, CA) through the right or left internal jugular vein. Cardiac output (CO) was measured by thermodilution using rapid bolus injection of 10 cc cold saline.
The average of five measurements were used. Systolic (sAP), diastolic (dAP), and mean arterial pressure (mAP) were measured automatically and noninvasively with the Dinamap XL (Johnson & Johnson Medical Inc, Arlington, VA). Pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG) were calculated using the following two formulas: TPG (mmHg) = mPAP – PCWP and PVR (WU) = TPG/CO. Pulmonary hypertension (PHT) was defined as PVR greater than 2.5 WU and(or) TPG greater than 12 mm Hg.
Every patient with PHT received a prostaglandin E1 infusion (Minprog 500; Pharmacia & Upjohn GmbH, Erlangen, Germany) over an infusion pump (Baxter Healthcare) using the distal lumen (pulmonary artery) of the Swan Ganz catheter. The infusion started with a dose of 10 ng/kg minute. After 5 minutes the hemodynamic monitoring was repeated. The prostaglandin E1 infusion was increased every 5 minutes in six steps to 20, 50, 70, 100, and 150 up to the maximum dose of 200 ng/kg per minute. Five minutes after every dose, uptitration hemodynamic testing was repeated. After reaching a PVR and TPG below the PHT criteria, the prostaglandin E1 infusion was stopped and the catheter was removed. The study protocol was approved by the institution's Investigational Review Board and all patients gave written informed consent before treatment.
Statistics
Results are presented as mean values ± standard deviation. A Fisher t test was used for comparison of continuous variables. The 
2 test was used for categoric variables, a log-rank test was used for Kaplan-Meier analyses, and p less than 0.05 was considered statistically significant. All statistical analysis was done using SPSS 11.5 (SPSS, Inc, Chicago, IL).
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Results
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In total, 217 patients who received orthotopic cardiac transplantation and in whom pretransplant hemodynamics were available were included in this study. In 49 patients (22.6%) PHT was evident. Patients from the rev-PHT group were significantly older (54.8 ± 9.8 vs 49.2 ± 12.3 years, p < 0.01), while the disease (dilative cardiomyopathy, 61% vs 65%) and gender (male, 75% vs 80%) were similarly distributed. The patients' hemodynamics are presented in Table 1.
The PVR, TPG, and pulmonary artery mean pressure could be significantly reduced during PG treatment. In comparison with the hemodynamics from the non-PHT group PVR could be reduced to similar values, while TPG, mean pulmonary artery (PAm), and PCWP were still significantly elevated (Fig 1), despite reaching values which make these patient eligible for orthotopic transplant.
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Fig 1. Kaplan-Meier survival curves in patients without pulmonary hypertension (PHT; bold line) and patients with reversible PHT (dashed line).
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Outcome After Orthotopic Cardiac Transplantation
All 217 underwent orthotopic cardiac transplantation. The Kaplan-Meier survival curve is depicted in Figure 1. While there is a nonsignificant difference in the 30-day survival, in the long term, after the first year, this difference is no longer detectable.
The reasons for death in the early phase after cardiac transplantation in both PHT groups are shown in Table 2. Acute right heart failure (RHF) was a significantly higher reason for death in the rev-PHT group (p = 0.035). Right heart failure as a reason of death occurred in 70% in the time interval 1996 to 2000 and in 0% from 2001 to 2005. Multiorgan failure (MOF) as a reason for death was comparable within the groups. Other reasons for death occurred less frequently.
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Comment
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We could show that elevated PVR and TPG, which are definitive contraindications for orthotopic cardiac transplantation, could be successfully reduced with prostaglandin E1 treatment in pretransplant evaluation. However, pulmonary pressures after reduction were still significantly elevated compared with the non-PHT group. This elevation affected the early outcome after cardiac transplantation. Notably, the incidence of acute RHF was significantly elevated in this group. Newer medical treatment in the operation room, especially the use of inhaled nitric oxide, and early postoperative care in the intensive care unit (ICU) have reduced the risk of RHF to 0% since 2001. Survival in the long term after transplantation was not affected by reversible PHT.
Previous studies showed that, in patients with congestive heart failure and pulmonary hypertension being assessed for cardiac transplantation, the administration of prostaglandin E1 significantly decreased PVR and TPG [5, 10–13, 17]. However, studies regarding mortality and the risk of right heart failure in the early and late terms after transplant in patients with reversible PHT are not conclusive. While Iberer and colleagues [17] could show no increased risk of RHF in patients with reversible PHT, Chen and colleagues reported an increased risk of mortality in the first 30 days after transplantation. In the recent publication from Butler and colleagues [14], mortality after transplantations was increased even in patients with reversible PHT in a mean follow-up of 42 ± 28 months. Tenderich and colleagues [18] showed an increased 30-day mortality but no impact on survival 5 years posttransplant, while Delgado and colleagues [6] could not see a negative effect of reversible PHT regarding the 30-day and 3-year mortality.
Although preoperative pulmonary hypertension is well-recognized as being associated with acute right ventricular failure after orthotopic transplantation, no general agreement has been reached on the level of pulmonary hypertension that most accurately predicts a poor postoperative outcome. In 1998 Kirklin and colleagues [19] reported that elevated preoperative PVR was the most important risk factor for early and late posttransplant mortality. The effect of PVR was continuous, such that there was a progressively incremental risk of death with increasing PVR. Later studies showed that elevated nonreversible preoperative PVR and TPG have been shown to be associated with a significant increase in both early and late posttransplantation death [2, 3, 5, 6, 20]. In 1990 Erickson and colleagues [3] showed that a PVR 2.5 WU or less and a TPG 12 mm Hg or less are not associated with higher posttransplant mortality. However, so far every cardiac transplant center has its own guidelines in evaluating and transferring patients to the transplant waiting list and neither the United Network for Organ Sharing (UNOS) nor the Eurotransplant Foundation (ET) have guidelines regarding the acceptance of patients with reversible pulmonary hypertension.
It is clear that unresponsive PHT is associated with higher mortality posttransplant. Therefore, knowing whether PHT is reversible in transplant candidates is crucial. In addition, a focus must be the perioperative, the operating room, and the ICU management in these high risk patients. We could show that acute RHF as a cause of death has not occurred since 2001. The knowledge of pulmonary vasodilatory drugs like inhaled nitro oxide [21, 22] or systemic infusion of prostaglandin derivates [11, 23] is essential for the outcome of these patients.
The pharmacologic testing of reversibility of pulmonary hypertension is an essential test in evaluation and selection of candidates for cardiac transplantation. Despite still higher values of PVR and TPG in comparison with patients without PHT cardiac transplantation can be performed safely. While the long-term outcome is not affected, the use of pulmonary vasodilator drugs perioperatively is the crucial step to reduce the risk of early right heart failure.
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References
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