Simulated Regionalization of Heart and Lung Transplantation in the United States.

We simulated the impact of regionalization of isolated heart and lung transplantation within United Network for Organ Sharing (UNOS) regions. Overall, 12 594 orthotopic heart transplantation (OHT) patients across 135 centers and 12 300 orthotopic lung transplantation (OLT) patients across 67 centers were included in the study. An algorithm was constructed that "closed" the lowest volume center in a region and referred its patients to the highest volume center. In the unadjusted analysis, referred patients were assigned the highest volume center's 1-year mortality rate, and the difference in deaths per region before and after closure was computed. An adjusted analysis was performed using multivariable logistic regression using recipient and donor variables. The primary outcome was the potential number of lives saved at 1 year after transplant. In adjusted OHT analysis, 10 lives were saved (95% confidence interval [CI] 9-11) after one center closure and 240 lives were saved (95% CI 209-272) after up to five center closures per region, with the latter resulting in 1624 total patient referrals (13.2% of OHT patients). For OLT, lives saved ranged from 29 (95% CI 26-32) after one center closure per region to 240 (95% CI 224-256) after up to five regional closures, but the latter resulted in 2999 referrals (24.4% of OLT patients). Increased referral distances would severely limit access to care for rural and resource-limited populations.

Splenic Irradiation for the Treatment of Severe Antibody-Mediated Rejection.

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody-mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long-term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor-specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short- or medium-term adverse effects of the radiation therapy. One-year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis.

Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. Therefore, we conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom. Patients with CF who underwent lung or heart-lung transplantation in the United States or United Kingdom between January 1, 2000 and December 31, 2011 were included. The primary outcome was all-cause mortality. Kaplan-Meier analysis and Cox proportional hazards regression evaluated the effect of healthcare system and insurance on mortality after LTx. 2,307 US LTx recipients and 451 individuals in the United Kingdom were included. 894 (38.8%) US LTx recipients had publically funded Medicare/Medicaid insurance. US private insurance and UK patients had improved median predicted survival compared with US Medicare/Medicaid recipients (p < 0.001). In multivariable Cox regression, US Medicare/Medicaid insurance was associated with worse survival after LTx (US private: HR0.78,0.68-0.90,p = 0.001 and UK: HR0.63,0.41-0.97, p = 0.03). This study in CF patients is the largest comparison of LTx in two unique health systems. Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, the performance of US public insurance is significantly worse and may put patients at risk.

Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation.

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

High-quality CMV-specific CD4+ memory is enriched in the lung allograft and is associated with mucosal viral control.

The maintenance of CMV-specific T cell memory in lung transplant recipients (LTRs) is critical for host defense and allograft durability, particularly in donor(+) /recipient(-) (D(+) R(-) ) individuals who demonstrate increased mortality. We studied CD4(+) and CD8(+) CMV-specific memory responses to phosphoprotein 65 (pp65) in a prospective cohort of 18 D(+) R(-) LTRs, from bronchoalveolar lavage (BAL)-obtained lung mononuclear cells (LMNC) and PBMC. Unexpectedly, pp65-specific CD4(+) and CD8(+) IFN-γ memory responses from LMNC were similar, in contrast to persistent CD8(+) predominance in PBMC. Unlike the pulmonary CD8(+) predominance during acute primary infection, compartmental equalization occurred in the CMV-specific CD8(+) memory pool during chronic infection, whereas CMV-specific CD4(+) memory was enriched in the bronchoalveolar space. Moreover, CMV-specific CD4(+) memory T cells with multifunctional production of IFN-γ, TNF-α, IL-2 and MIP-1ß were significantly increased in LMNCs, in contrast to similar intercompartmental CD8(+) memory function. Moreover, the absolute number of CMV-specific CD4(+) IFN-γ(+) memory cells in BAL was significantly increased in LTRs exhibiting viral control compared to those with CMV early antigen positivity. Collectively, these data demonstrate both preferential distribution and functional quality of CMV-specific CD4(+) memory in the lung allograft during chronic infection, and show an important association with CMV mucosal immunity and viral control.

Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Elevated plasma clara cell secretory protein concentration is associated with high-grade primary graft dysfunction.

Primary graft dysfunction (PGD) is the leading cause of early posttransplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the nonciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pretransplant and 6 and 24 h posttransplant. The primary outcome was the development of grade 3 PGD within the first 72 h after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 h. The median CC16 level 6 h after transplant was significantly higher in patients with PGD [13.8 ng/mL (IQR 7.9, 30.4 ng/mL)] than in patients without PGD [8.2 ng/mL (IQR 4.5, 19.1 ng/mL)], p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.

CD154 deficiency uncouples allograft CD8+ T-cell effector function from proliferation and inhibits murine airway obliteration.

Obliterative bronchiolitis (OB) limits the long-term success of lung transplantation, while T-cell effector mechanisms in this process remain incompletely understood. Using the murine heterotopic tracheal transplant model of obliterative airway disease (OAD) to characterize airway allograft rejection, we previously reported an important role for CD8(+) T cells in OAD. Herein, we studied the role of CD154/CD40 costimulation in the regulation of allospecific CD8(+) T cells, as airway rejection has been reported to be CD154-dependent. Airway allografts from CD154(-/-) recipients had significantly lower day 28 OAD scores compared to wild-type (WT) recipients, and adoptive transfer of CD8(+) T cells from WT recipients, but not CD154(-/-) recipients, were capable of airway rejection in fresh CD154(-/-) allograft recipients. Intragraft CD8(+) T cells from CD154(-/-) mice showed similar expression of the surface markers CD69, CD62L(low) CD44(high) and PD-1, but markedly impaired IFN-gamma and TNF-alpha secretion and granzyme B expression versus WT controls. Unexpectedly, intragraft and systemic CD8(+) T cells from CD154(-/-) recipients demonstrated robust in vivo expansion similar to WT recipients, consistent with an uncoupling of proliferation from effector function. Together, these data suggest that a lack of CD154/CD40 costimulation results in ineffective allospecific priming of CD8(+) T cells required for murine OAD.

Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation.

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

Plasma intercellular adhesion molecule-1 and von Willebrand factor in primary graft dysfunction after lung transplantation.

Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM-1 and vWF. At each postoperative timepoint, mean plasma ICAM-1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM-1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM-1 are associated with PGD following lung transplantation.

Lung transplantation for pulmonary hypertension.

Lung transplantation is an accepted therapeutic intervention for patients with pulmonary arterial hypertension (PAH) who fail medical therapy. Highly selected candidates with PAH may enjoy improved survival by combining medical therapy with transplantation. Despite the known benefits of lung transplantation that include improvement in haemodynamics, exercise tolerance, shortness of breath and long-term survival, this intervention is associated with significant shortcomings. These include, the need for lifelong immunosuppression, and the morbidity associated with the increased risk for infection and allograft rejection. To maximise the potential outcomes of lung transplantation, candidates should be selected based on the international guidelines developed by a consensus panel of experts in the field (J Heart Lung Transplant, 25, 2006, 745). Early referral to a centre with expertise in the management of PAH and transplantation increases the chances of achieving the best possible long-term outcome for patients with this devastating disease.

Thoracic organ transplantation in the United States, 1995-2004.

This article reviews trends in thoracic organ transplantation based on OPTN/SRTR data from 1995 to 2004. The number of active waiting list patients for heart transplants continues to decline, primarily because there are fewer patients with coronary artery disease listed for transplantation. Waiting times for heart transplantation have decreased, and waiting list deaths also have declined, from 259 per 1000 patient-years at risk in 1995 to 156 in 2004. Fewer heart transplants were performed in 2004 than in 1995, but adjusted patient survival increased to 88% at 1 year and 73% at 5 years. Emphysema, idiopathic pulmonary fibrosis and cystic fibrosis were the most common indications among lung transplant recipients in 2004. Waiting time for lung transplantation decreased between 1999 and 2004. Waiting list mortality decreased to 134 per 1000 patient-years at risk in 2004. One-year survival following transplantation has improved significantly in the past decade. The number of combined heart-lung transplants performed in the United States remains low, with only 39 performed in 2004. Overall unadjusted survival, at 58% at 1 year and 40% at 5 years, is lower among heart-lung recipients than among either heart or lung recipients alone.

Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness.

The success of lung transplantation has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. However, significant improvement for the overall outcomes of lung transplantation will only occur when better methods exist to prevent or effectively treat chronic rejection.

Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab.

BACKGROUND: Because acute rejection is associated with inferior outcomes in lung transplantation, we have routinely employed OKT3, anti-thymocyte globulin (ATG), or daclizumab as adjuncts to reduce rejection. METHOD: We performed a 4-year prospective, controlled clinical trial of these 3 therapies to determine differences in post-operative infection, rejection, survival, and bronchiolitis obliterans syndrome (BOS). Eighty-seven consecutive lung transplant patients received OKT3 (n = 30), ATG (n = 34), and daclizumab (n = 23) as induction agents. The groups had similar demographics and immunosuppression protocols differing only in induction agents used. RESULTS: No differences were observed in immediate post-operative outcomes such as length of hospitalization, ICU stay, or time on ventilators. Twelve months post-transplant, OKT3 had more infections per patient than the other agents, a difference that only became significant 2 months post-operatively (p = 0.009). The most common infection was bacterial and OKT3 had more bacterial infections than any other agent. Daclizumab had more patients remain infection free in the first year (p = 0.02), having no fungal infections and a low rate of viral infections. No patient receiving daclizumab developed drug specific side-effects. Only those patients with episodes of acute rejection developed BOS. There were no significant differences in the freedom from acute rejection or BOS between the groups. The 2-year survival for the entire cohort was 68%, with no differences observed in patient survival. CONCLUSIONS: This study again reveals the importance of acute rejection in the subsequent development of BOS. Although daclizumab offers a low risk of post-transplant infection and drug specific side-effects, no drug is superior in delaying rejection or BOS or in prolonging long-term survival.

Patterns and significance of exhaled-breath biomarkers in lung transplant recipients with acute allograft rejection.

BACKGROUND: Obliterative bronchiolitis (OB) remains one of the leading causes of death in lung transplant recipients after 2 years, and acute rejection (AR) of lung allograft is a major risk factor for OB. Treatment of AR may reduce the incidence of OB, although diagnosis of AR often requires bronchoscopic lung biopsy. In this study, we evaluated the utility of exhaled-breath biomarkers for the non-invasive diagnosis of AR. METHODS: We obtained breath samples from 44 consecutive lung transplant recipients who attended ambulatory follow-up visits for the Johns Hopkins Lung Transplant Program. Bronchoscopy within 7 days of their breath samples showed histopathology in 21 of these patients, and we included them in our analysis. We measured hydrocarbon markers of pro-oxidant events (ethane and 1-pentane), isoprene, acetone, and sulfur-containing compounds (hydrogen sulfide and carbonyl sulfide) in exhaled breath and compared their levels to the lung histopathology, graded as stable (non-rejection) or AR. None of the study subjects were diagnosed with OB or infection at the time of the clinical bronchoscopy. RESULTS: We found no significant difference in exhaled levels of hydrocarbons, acetone, or hydrogen sulfide between the stable and AR groups. However, we did find significant increase in exhaled carbonyl sulfide (COS) levels in AR subjects compared with stable subjects. We also observed a trend in 7 of 8 patients who had serial sets of breath and histopathology data that supported a role for COS as a breath biomarker of AR. CONCLUSIONS: This study demonstrated elevations in exhaled COS levels in subjects with AR compared with stable subjects, suggesting a diagnostic role for this non-invasive biomarker. Further exploration of breath analysis in lung transplant recipients is warranted to complement fiberoptic bronchoscopy and obviate the need for this procedure in some patients.

Lung transplantation for primary and secondary pulmonary hypertension.

BACKGROUND: Single lung transplantation (SLT) and bilateral lung transplantation (BLT) are routinely performed in patients with primary pulmonary hypertension (PPH) and secondary pulmonary hypertension (SPH). It is unclear which procedure is preferable. We reviewed our experience with lung transplants for PPH and SPH to determine if any advantage exists with SLT or BLT for either PPH or SPH. METHODS: We reviewed the outcomes of all lung transplants performed for PPH or SPH for 4.5 years (July 1995 to January 2000). Survival was reported by the Kaplan-Meier method, and log rank analysis was used to determine significance. Statistical analyses of clinical data were performed using analysis of variance and chi2 analysis. RESULTS: A total of 57 recipients met criteria for pulmonary hypertension with a mean pulmonary artery pressure of greater than or equal to 30 mm Hg. There were 15 patients with PPH and 40 patients with SPH. There were 6 patients who had SLTs and 9 patients who had BLTs in the PPH group; and there were 9 patients who had SLTs and 21 patients who had BLTs in the SPH group. We found a survival advantage for PPH patients who underwent BLTs at all time points up to 4 years (100% vs 67%; p < or = 0.02). There was no clear advantage to SLTs or BLTs for SPH. At 4 years there was a trend toward improved survival with SLTs (91% vs 75%) in SPH patients with a mean pulmonary artery pressure less than or equal to 40 mm Hg (p < or = 0.11) with equivalent survival (80%) in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg. There was also a trend toward improved survival in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg (PPH and SPH) with BLTs (88% vs 62%; p = 0.19). The incidence of rejection, infection, and other complications was comparable between SLTs and BLTs in each group. CONCLUSIONS: We believe that BLT is the procedure of choice for PPH. The procedure of choice is less clear for SPH. Patients with SPH and a mean pulmonary artery pressure greater than 40 mm Hg may benefit from a BLT and those with a mean pulmonary artery pressure less than or equal to 40 mm Hg may do better with an SLT; however, no clear advantage is seen.

Lung transplantation for pulmonary hypertension.

Although lung transplantation is a viable option for patients with end-stage pulmonary hypertension, it is associated with numerous problems including infection, rejection, and limited long-term survival. Because of these limitations, transplantation should only be considered for patients who are failing maximal medical therapy. Treatment options for patients with pulmonary hypertension that may serve to prolong or obviate the need for transplantation include anticoagulation with warfarin, diuretics, and vasodilators such as calcium channel blockers or continuous intravenous epoprostenol (prostacyclin). The response to medical therapy should be assessed at regular intervals by evaluating exercise tolerance and hemodynamic parameters. Because waiting periods for transplantation now exceed 1.5 to 2 years in the United States, and the response to medications is unpredictable, referral for transplantation should occur when patients become symptomatic. Those who are responding well to medical therapy should be removed from the active transplant waiting list, whereas those who fail therapy should go on to transplant. Utilizing medical therapy and transplantation as complementary treatments will achieve the best potential to improve quality of life and prolong survival.