JHLT highlights 2011: Cardiothoracic transplantation, pulmonary hypertension, and mechanical circulatory support

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JHLT highlights 2011: Cardiothoracic transplantation, pulmonary hypertension, and mechanical circulatory support Pali Shah, MD,a Daniel Tang, MD,b Keyur Shah, MD,c and Mandeep R. Mehra, MDd From the aDivision of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland; the bDivision of Cardiothoracic Surgery, Virginia Commonwealth University Hospital System, Richmond, Virginia; cDivision of Cardiology, Virginia Commonwealth University Hospital System, Richmond, Virginia; and the dDepartment of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

The year 2011 brought exciting advances in the field of cardiothoracic transplantation, pulmonary hypertension, and mechanical circulatory support. Although a review of each noteworthy publication is beyond the scope of one article, in this report, we highlight 9 articles published this year in the Journal of Heart and Lung Transplantation, that broadly reflect the state of the respective fields in translational, clinical, and epidemiologic research. These articles were selected for their ability to further our understanding of each field and stimulate ongoing scientific inquiry to improve outcomes for these patients.

Lung transplantation Emerging evidence suggests heterogeneity in the phenotype of chronic allograft dysfunction, which has primarily been defined as bronchiolitis obliterans syndrome (BOS), a progressive lung disease with obstructive physiology.1–3 In a cohort of 493 lung transplant recipients, Sato et al4 described a distinct phenotype of ‘‘restrictive allograft syndrome (RAS)’’characterized with chronic lung allograft dysfunction (CLAD) in the setting of restrictive physiology. RAS was defined as an irreversible decline in total lung capacity to o 90% of baseline in patients who also met criteria for CLAD, previously defined by an irreversible decline in forced expiratory volume in 1 second (FEV1) to o 80% of baseline. A RAS phenotype was demonstrated in 30% of patients, with the remaining classified as BOS. Compared with patients with BOS, Patients with RAS were Reprint requests: Pali Shah, MD, Johns Hopkins University School of Medicine, 1830 Monument St, 5th Flr, Baltmore, MD 21201. Telephone: 410-955-3467. Fax: 410-955-0036. E-mail address: [email protected]

significantly more likely to show computed tomography scan findings of interstitial lung disease, with 41% displaying upper-lobe fibrosis (p o 0.00001). Lung pathology, when available, was suggestive of interstitial fibrosis and increased myofibroblasts in the RAS group. Patients who developed RAS had significantly worse survival than patients with BOS or without any CLAD, with a median survival of only 1.5 vs 3.9 years (p o 0.0003). This study has distinguished 2 distinct phenotypes of CLAD on the basis of physiologic changes, with significant implications for prognosis. As a retrospective, single-center study, further validation is needed in a prospective multicenter cohort, particularly with respect to radiographic changes and pathology. This study also excluded singlelung transplant recipients due to confounding effects of the native lung in measuring total lung capacity. Further investigations into risk factors for RAS may help the development of strategies to prevent or treat this aggressive form of chronic allograft dysfunction. In another thought-provoking article regarding the pathogenesis of BOS, Saini et al5 examined the relationship between alloimmune and autoimmune responses in a retrospective study of 20 patients positive for BOS (BOSþ) and 22 controls negative for BOS (BOS–) controls. The development of donor-specific antibodies (DSA) to mismatched human leukocyte antigens has been associated with BOS. Independently, detection of antibodies to self-antigens K-a1 tubulin (KaT) or type V collagen (ColV) have been associated with BOS, leading to a hypothesis that exposure of these otherwise ‘‘hidden’’ antigens during allograft injury triggers a pathologic autoimmune response.6–8 In this prospective study of 103 patients, DSA developed in 42% of lung transplant recipients, and 75% of patients who developed DSA also had detectable autoantibodies

1053-2498/$ - see front matter r 2012 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2012.09.028

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(auto-AB) to KaT or ColV. Patients who were DSAþ and auto-ABþ comprised 26% of all patients with BOS. Analysis of serial serum suggested that DSA preceded the development of auto-AB and that auto-AB persisted without detectable DSA. Although auto-ABs were detected in 12.6% of patients who did not have DSA, the concentration of auto-AB in BOSþ/DSAþ recipients was 2-fold higher than that in BOS–/DSA– recipients (p o 0.05 for both KaT and ColV). A comparison of enzyme-linked immunospot-based cytokine profiles in BOS– and BOSþ patients revealed a shift in ColV-specific T cells, with increased frequencies of interleukin (IL)-10 secretion in BOS– patients (p o 0.05) to increased interferon (IFN)-g (p o 0.05) and IL-17 secretion (p o 0.01) in BOSþ patients. This study is the first to provide evidence linking the detection of humoral autoimmune responses to the development of autoimmune responses associated with BOS. However, because there is center-specific variation in reported prevalence of DSA after transplant, validation of the detected alloantibodies and autoantibodies by other investigators would strengthen the role of these pathways in the pathogenesis of BOS. Ongoing dissection of the mechanisms by which alloimmune responses trigger pathologic autoimmune responses may lead to novel therapeutic targets for the prevention of BOS. Cytomegalovirus (CMV) exposure has been an important risk marker for chronic allograft dysfunction and long-term survival in lung transplant recipients.9,10 Although results of a recent prospective, randomized controlled trial suggested a reduced incidence of early CMV disease with 12 months of anti-viral prophylaxis compared with 3-month prophylaxis, the long-term benefit of this strategy was unknown.11 In a follow-up to this trial, Finlen Copeland et al12 report longterm outcomes in a single-center sub-set of 38 patients from the original study. Median duration of follow-up was 3.9 years in short-course and extended-prophylaxis groups. The incidence of active CMV was markedly reduced in the extended-prophylaxis group compared with the short-course group (12% vs 55%, p o 0.002), which was independent of CMV serologic status, time to use of Thymoglobulin (Genzyme Transplant, Cambridge, MA), or acute rejection. There were no significant differences in the hematologic cell counts between groups. However, despite a reduced incidence of CMV disease, no significant difference was found in the incidence of BOS (38% vs 43%) or overall mortality (41% vs 35%) between the groups. Although the use of a single-center sub-set limits the ability to generalize these results to other centers due to the possibility that center-specific practices have affected the results, this is the first randomized controlled study to show long-term protection against CMV disease with extendedduration prophylaxis in high-risk lung transplant recipients. Interestingly, although this study was not powered for mortality differences, the trends do not suggest improved survival with extended prophylaxis, raising broader questions about unmeasured sequelae of CMV or its treatment. Thus, further research is needed to determine whether freedom from CMV disease confers a survival benefit or reduction in chronic allograft dysfunction in this population.

Pulmonary hypertension The outcome of patients with pulmonary arterial hypertension (PAH) appears to have improved in the era of pulmonary vasodilator therapy, but ethical concerns and sample size requirements have limited prospective survival studies using these therapies.13–15 Benza et al16 used a database of 811 PAH patients receiving sub-cutaneous treprostinil in randomized controlled trials to identify determinants of survival at baseline and on therapy. After completing a univariate analysis, multivariate analyses were conducted to determine independent predictors of survival among baseline variables and on-treatment variables measured at 12 weeks. The baseline factors associated with death were body mass index in decrements of 10 years (hazard ratio [HR], 0.52; p o 0.001), creatinine (HR, 1.73; p o 0.001), low albumin (HR, 0.70; p o 0.001), and bilirubin (HR, 1.02; p o 0.03). On-treatment factors associated with survival were increased treprostinil dose (HR, 0.64; p o 0.009), with a threshold dose identified at 40 ng/kg/min, improved 6-minute walk distance (HR, 0.86; p o 0.004), with a threshold walk distance identified at 295 meters, and improved mixed venous oxygenation (HR, 0.66; p o 0.018). This study supports earlier observations that baseline disease etiology, pulmonary hemodynamics, and other comorbidities are significantly associated with survival in PAH. Because of the retrospective nature of the study, no data were available for patients who discontinued treprostinil. In addition, there are insufficient data on dose titrations or adjunct therapies after the initial 12 weeks to determine the potential effect of these changes on long-term survival. However, the survival inflection associated with a threshold dose of treprostinil and the 6-minute walk distance may guide clinicians in titrating therapy and considering alternate options for non-responders.

Heart transplantation Within heart transplantation, notable reports highlighted standardization in the diagnosis of antibody-mediated rejection (AMR), the use of a complement-binding sub-set of DSA to predict AMR, and the effects of late conversion from calcineurin inhibitors to proliferation signal inhibitors. The diagnosis of AMR was previously based on the constellation of clinical allograft dysfunction, circulating DSA, and histopathologic and immunophenotypic findings.16 However, there has been continued variability among transplant centers in the pathologic techniques and diagnostic criteria for defining AMR. Berry et al17 reported the findings of a consensus conference held in conjunction with the 2010 International Society for Heart and Lung Transplantation 30th Annual Meeting and updates the previous working formulation. The primary recommendation from the working group was that AMR be exclusively a pathologic diagnosis, paralleling the standards for acute cellular rejection. A grading system was proposed incorporating histopathology and immunopathology (Table 1), and clinical

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JHLT Highlights From 2011

Table 1 Proposed International Society for Heart and Lung Transplantation Criteria for the Diagnosis of Antibody-Mediated Rejection pAMR pathologic grade 0 1 (Hþ)a 1 (Iþ)b 2 3

Findings No histopathologic or immunopathologic evidence of antibody-mediated rejection Histology positive, immunopathology negative Immunopathology positive, histology negative Histology and immunopathology are positive Severe histopathologic findings of marked edema, interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis or karyorrhexis

pAMR, pathologic antibody-mediated rejection. a þ H (histology positive) may include endothelial edema, intravascular macrophage accumulation, interstitial edema, hemorrhage, intravascular thrombi, and myocyte necrosis. b þ I (immunopathology positive) may include immunohistochemistry and immunofluorescent for immunoglobulins, complement and macrophages.

evidence of allograft dysfunction and circulating DSA were no longer required for the diagnosis of AMR. The effect of this change was to acknowledge the existence of asymptomatic AMR as well as AMR without circulating DSA. The authors also put forth basic guidelines for immunostaining techniques, partly addressing issues with the wide interinstitution variability for biopsy preparation and surveillance protocols (Table 2). This document represents an evolutionary step in the pathologic standardization of the diagnosis of AMR and formally acknowledges the existence of asymptomatic AMR. How these various sub-sets should be followed or treated requires further work. Although the presence of DSA was removed from the pathologic diagnosis of AMR, DSA remains central to its pathophysiology. However, current assays for DSA identify HLA antibodies that may not necessarily lead to graft injury. Table 2 Guidelines for Paraffin Immunohistochemistry and Frozen Section Immunofluorescent Techniques for AntibodyMediated Rejection 













Immunohistochemistry (IC) should include C4d staining, while the use of other markers such as CD68 was encouraged The recommended primary panel for immunofluorescent (IF) staining was limited to C3d and C4d Only interstitial capillaries should be assessed on complement staining Complement staining should be avoided for the first 2 weeks after transplantation Surveillance biopsies are recommended at 2 and 4 weeks and thereafter are deferred to center preference Once a biopsy specimen is positive for immune staining, IC/ IF should be continued on subsequent biopsy specimens until a negative result is obtained Multifocal or diffuse staining of complement is required for diagnosis

1259 One potential mechanism for these conflicting outcomes is variation in complement activation by the DSA. Chin et al18 reported use of a novel assay to identify the sub-set of HLA immunoglobulin (Ig) G antibodies that bind the C1q component of the complement cascade and reported the association with AMR in pediatric heart transplantation. This was a retrospective study of 18 pediatric heart transplant recipients at a single center. Based on virtual crossmatching, the presence of pre-transplant and posttransplant HLA IgG DSA and C1q DSA were compared with the development of AMR in the first month after transplant. The 5 patients who developed AMR early after transplant had detectable C1q DSA. In contrast, none of the patients without detectable C1q DSA after surgery developed early AMR, despite a great proportion of patients having positive virtual crossmatches and/or detectable IgG DSA after transplant. Pre-transplant testing of C1q DSA, however, did not necessarily predict the post-transplant detection of the antibody. This was a very small cohort of 18 pediatric heart transplant recipients, and certainly, largerscale studies are needed. Nonetheless, the presence of positive C1q DSA at the time of biopsy had a striking association with AMR (100% positive predictive value, negative predictive value, sensitivity, and specificity). This study suggests that classification of HLA antibodies by their functional component can help distinguish antibodies that are clinically significant. This study further demonstrates that the production of HLA antibody with the ability to fix complement is a dynamic process and can change quickly in the peri-operative period. Many centers transition from calcineurin inhibitors (CNI) to proliferation signal inhibitors (PSI) to prevent or treat renal dysfunction. However, the benefits of CNI to PSI conversion late after heart transplantation are poorly defined. Gonzalez-Vilchez et al19 evaluated the effects of late-term conversion from CNI to PSI on renal function in heart transplantation. The investigators studied 49 consecutive patients who underwent late term conversion from CNI (41 cyclosporine, 8 tacrolimus) to PSI (21 sirolimus, 28 everolimus) at 9 ⫾ 4 years after transplant. During the 28 ⫾ 13 months of follow-up after conversion to a PSI, 16% of patients experienced acute allograft rejection, 37% were intolerant of the PSI, and 18% died. Changes in renal function were assessed at 1 year after conversion and at the end of follow-up. Baseline glomerular filtration rate (40.2 ⫾ 22.2 ml/min/1.73 m2) remained stable at 1 year (41.3 ⫾ 22.4 ml/min/1.73 m2) but decreased significantly at the end of follow-up (35.5 22.3 ml/min/1.73 m2, p ¼ 0.008). In a multivariate analysis, diabetes and the absence of therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) were significant predictors for a decline in renal function. Prior studies supporting conversion to a PSI as an effective strategy to treat CNI-induced nephrotoxicity have been limited to earlier conversions and evaluated short-term outcomes.20,21 This article suggests that late-term conversion may not prevent long-term renal dysfunction, particularly in diabetic patients. Even more concerning was the unusually high rate of acute rejection after conversion in a

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population that was nearly a decade from the time of transplantation. Although this was a retrospective study without a control group, these data would caution against routine late conversion until properly controlled studies are performed. Furthermore, patients undergoing conversion to a PSI any time after transplantation should be subject to heightened surveillance for allograft rejection. The observation that ACE/ARBs may be protective, possibly by reducing proteinuria, is provocative and certainly warrants study in a controlled model.

Mechanical circulatory support The use of left ventricular assist devices (LVADs) continues to grow exponentially. Two notable articles from 2011 are highlighted for the risk stratification of LVAD patients and the use of proteomic profiling to study ventricular remodeling after LVAD implantation. In the report ‘‘Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification,’’ Boyle et al22 reported the effect illness severity on outcomes after LVAD. This was a retrospective study of 101 consecutive LVAD patients at 3 centers. Patients were stratified into 3 groups by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile: Group 1, cardiogenic shock (profile 1); Group 2, inotrope-dependent (profiles 2 and 3); and Group 3, non–inotrope-dependent outpatients (profiles 4 through 7). Not surprisingly, the non–inotropedependent patients had better outcomes. These patients had a shorter length of stay (17 ⫾ 14 days in Group 3 vs 44 ⫾ 58 days in vs Group 1 [p o 0.001] and 41 ⫾ 39 days in Group 2, p o 0.001) and superior long-term survival at 36 months compared with cardiogenic shock patients (96% in Group 3 vs 51% in Group 1, p ¼ 0.011). There was a trend for improved survival between Group 3 (96%) and Group 2 (69%, p ¼ 0.065). As the survival for LVAD patients continues to improve, there has been increased interest in the use of LVADs in less ill patients. The remarkably improved outcomes and short hospital lengths of stay in the non-inotrope group are eyecatching, especially during these cost-conscious economic times where implanting programs are scrutinized for clinical as well as fiscal outcomes. However, little data are available to guide the assessment of risk-to-benefit for LVAD implantation in the stable non–inotrope-dependent heart failure patient. Although this retrospective study included 24 such patients, we must await the completion of more comprehensive comparative studies in larger cohorts before drawing any firm conclusions. The mechanisms of myocardial remodeling after LVAD implantation remain poorly understood. Changes in gene expression after LVAD implantation have been reported, but this does not necessarily correlate with changes in protein expression. De Weger et al23 used proteomic profiling to study LV remodeling after LVAD implantation. They studied tissue from 11 LVAD patients (5 with ischemic cardiomyopathy [ICM], 6 with dilated cardiomyopathy [DCM]) taken from the LV apical core at implant and

adjacent LV wall at transplantation. Findings were compared with tissue from 5 reference patients (2 organ donors, 3 autopsy specimens). Fluorescent 2-dimensional difference gel electrophoresis was used to identify proteins that were upregulated or downregulated 1.5-fold. Distinct differences in the protein profiles of DCM and ICM patients were found. Of 1,400 to 1,700 proteins: 16 were downregulated in DCM, and 38 were downregulated and 12 were upregulated in ICM. At the time of transplant, both groups demonstrated protein expression profiles similar to the reference group, and approximately 66% of these proteins were related to cytoskeleton and mitochondrial energy metabolism. Electron microscopy demonstrated significant associated alternations in mitochondrial morphology. One protein, a-1-antichymotrypsin, thought to have a role in heart failure–related inflammation, was identified as being prominently downregulated in ICM and DCM. The authors then confirmed this finding in a separate larger cohort of 14 DCM and 15 ICM patients using an enzyme-linked immunosorbent assay. In contrast to other ‘‘omics’’ type studies, where one is often left with a dazzling mosaic of data and unclear clinical significance, the authors were able to identify a potential sub-cellular protein basis for remodeling. They then extended their findings to a potential novel biomarker for remodeling. This study, while offering an advance in our understanding of the cellular physiology of recovery, requires translation to the realm of clinical recovery, a notion that has continued to evade us until now.

Summary These few highlights represent a mere microcosm of the intense investigational activity in our field of advanced heart and lung therapy. The Journal has continued to enjoy an eminence in this space, and its demonstrated 2011 Impact Factor of 4.332 (a 26% increase over 2010), as well as dramatic rise in submissions, remains a testimony to the ongoing evolution in our field. This summary provides a mere glimpse into the vast ocean of discovery that affects refinements in diagnostics and therapeutics that change the lives of our patients with advanced stages of heart and lung failure.

Disclosure statement Dr Mehra reports consulting activity with NIH, St. Judes, Medtronic, Abbott Vascular, and Boston Scientific. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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