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Preponderance and implications of etiologic misclassification in advanced heart failure: A clinical-pathologic investigation
268
The Journal of Heart and Lung Transplantation, Vol 32, No 2, February 2013
lung epithelial and mesenchymal cells, it is an infrequent event. Furthermore, it suggests that recipient myofibroblasts are not the predominant proliferating element of bronchiolitis obliterans. From a pathogenetic perspective, our findings show that an alloreactive phenomenon with secondary epithelial injury represents the primary event rather than a primary uncontrolled proliferation of host mesenchymal stem cells at a site of injury. This is in contrast to bone marrow transplant studies showing that injury to and repair of lung parenchyma resulted in colonization of the lung by transdifferentiated hematopoietic stem cells.4,12 There are several possible explanations for the differences between our studies and others. First, selection pressures on transdifferentiated cells in the organ allografts examined may not have been strong enough to illicit the clonal expansion seen in experimental models and in the other studies. These transdifferentiated cells may be abnormal or fragile and have a limited replicative capacity and/or short lifespan. It is possible that these cells were not sampled in 2 of our patients, who were relatively long-term lung transplant survivors (42 years post-transplantation). Local differences and immunosuppression regimens or other treatment policies may interfere with transdifferentiation. Further, transdifferentiation may not be as common as originally described or hypothesized. In conclusion, in this small study we have investigated epithelial and mesenchymal microchimerism in gendermismatched lung allograft recipients. In our experience, there is very limited replacement of donor endothelium and small airway epithelium by recipient stem cells showing transdifferentiation into epithelial and mesenchymal elements. Furthermore, in our experience, the proliferating mesenchymal elements occurring as part of the chronic fibrosing rejection process in bronchiolitis obliterans represent donor myofibroblasts rather than myofibroblasts derived from recipient mesenchymal stem cells.
Disclosure statement The authors have no conflicts of interest to disclose. We thank Diana Winters for secretarial assistance. This study was approved by UPMC IRB # 0411036.
References 1. Suratt BT, Cool CD, Serls AE, et al. Human pulmonary chimerism after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003;168:318-22. 2. Mattsson J, Jansson M, Wernerson A, et al. Lung epithelial cells and type II pneumocytes of donor origin after allogeneic hematopoietic stem cell transplantation. Transplantation 2004;78:154-7. 3. Brocker V, Langer F, Fellous TG, et al. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med 2006;173:1276-82. 4. Kleeberger W, Versmold A, Rothamel T, et al. Increased chimerism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury. Am J Pathol 2003;162:1487-94. 5. Spencer H, Rampling D, Aurora P, et al. Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation. Thorax 2005;60: 60-2.
6. Badri L, Murray S, Liu LX, et al. Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2011;183:1062-70. 7. Borthwick DW, Shahbazian M, Krantz QT, et al. Evidence for stemcell niches in the tracheal epithelium. Am J Respir Cell Mol Biol 2001;24:662-70. 8. Brazelton TR, Shorthouse R, Huang X, et al. Infiltrating recipient mesenchymal cells form the obliterative airway disease lesion and dramatically remodel graft tissue in a model of chronic lung rejection. Transplant Proc 1997;29:2614. 9. Martinu T, Palmer SM, Ortiz LA. Lung-resident mesenchymal stromal cells. A new player in post-transplant bronchiolitis obliterans syndrome? Am J Respir Crit Care Med 2011;183:968-70. 10. Walker N, Badri L, Wettlaufer S, et al. Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts. Am J Pathol 2011;178:2461-9. 11. Kubit V, Sonmez-Alpan E, Zeevi A, et al. Mixed allogeneic chimerism in lung allograft recipients. Hum Pathol 1994;25:408-12. 12. Herzog EL, van Arnam J, Hu B, et al. Threshold of lung injury required for the appearance of marrow-derived lung epithelia. Stem Cells 2006;24:1986-92.
Preponderance and implications of etiologic misclassification in advanced heart failure: A clinical-pathologic investigation Lushna M. Mehra and Patricia A. Uber, BS, Pharm D From the University of Maryland School of Medicine, Baltimore, Maryland
The clinical classification of heart failure that demarcates etiology into ischemic and non-ischemic cardiomyopathy is suggested to guide therapy. Typically, those with an ischemic substrate demonstrate a worse prognosis and are considered candidates for treatment strategies targeted toward modification of the ischemic substrate. Because considerable overlap in these diagnostic strata exists and the extent of clinical misclassification remains uncertain, we sought to review the preponderance and implications of such misclassification by reviewing the final pathologic diagnosis in those hearts available after explantation due to heart transplantation. During a 20-month duration, 112 patients with the clinical etiologic diagnosis of non-ischemic cardiomyopathy (confirmed by a heart failure specialist) underwent heart transplantation at a single center. Patients were excluded if they were aged o 35 years, had congenital or familial heart disease, active myocarditis, peripartum cardiomyopathy, primary valvular heart disease or infiltrative heart disease. The recipient heart was examined histopathologically, and a pathologist blinded to clinical information classified the etiology of heart failure. Ischemic cardiomyopathy was defined as the presence of severe 3-vessel coronary disease (CAD) with myocardial scar. This definition was derived from the analysis of 51 control hearts with ischemic cardiomyopathy confirmed on pathologic analysis. Pathologic analysis of the presence of significant CAD and myocardial ischemia (ante-mortem) was also evaluated. The 112 patients (71% men; aged 57 ⫾ 9 years) in the study had severe ventricular dysfunction (left ventricular ejection fraction, 19% ⫾ 11%) and non-ischemic
Research Correspondence cardiomyopathy as the principle clinical diagnosis at the time of cardiac transplant. Of these, 23 (21%) were reclassified pathologically as ischemic cardiomyopathy. Of the remaining 89 who were accurately classified, 29 (33%) had at least moderate–severe CAD in 4 1 vessel territory, with or without infarction. In addition, 16 explanted hearts (18%) that were appropriately classified were noted to have areas compatible with recent ischemia, as noted by occlusive thrombus or ischemic infarction. The patients with etiologic misclassification were older (59 ⫾ 7 vs 53 ⫾ 8 years, p ¼ 0.001) and had a shorter interval from listing to transplantation (44 vs 58 months, p ¼ 0.05). This investigation suggests a high prevalence of etiologic misclassification in advanced heart failure. The clinical diagnosis of non-ischemic cardiomyopathy typically depends on the presence of a non-ischemic non-invasive evaluation or is established by coronary angiography. Although invasive angiography represents a general gold standard, intravascular ultrasound studies in native and non-native atherosclerosis have demonstrated the relative insensitivity of this approach.1 Diffuse CAD, as noted in patients with diabetes mellitus or in cardiac allograft vasculopathy, are glaring examples of the insensitivity of routine angiography, which greatly underestimates the potential pathologic contribution of concomitant coronary arteriopathy to disease progression and might steer the clinician away from opportunities for therapeutic intervention. Other pathologic studies have alluded to the presence of ischemic events in patients otherwise classified as nonischemic in etiology. Data from 2 clinical trials suggest the hypothesis that coronary thrombosis, which is mostly silent and consequently misdiagnosed, may be considered another potential mechanism, in addition to arrhythmias, that may explain the high rate of sudden death in non-ischemic heart
269 failure.2,3 However, one could argue that anti-platelet, anticoagulation, and lipid-modifying therapy has not been demonstrated to be disease-modifying, and therefore, this misclassification may not have clinical relevance. Conversely, it may be argued that the morbidity that accrues from events that exemplify the progression of heart failure, such as episodes of decompensation, may indeed be modified by the application of anti-ischemic preventative therapy, a concept that may deserve greater exploration in the setting of a large evidence-forming trial. In summary, this clinical-pathologic study has pointed to a high clinical misclassification rate as well as in the direction that ignoring anti-ischemic therapeutic strategies in ‘‘non-ischemic’’ heart failure may be unwise.
Disclosure statement None of the 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.
References 1. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy–2010. J Heart Lung Transplant 2010;29:717-27. 2. Uretsky BF, Thygesen K, Armstrong PW, et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial. Circulation 2000;102:611-6. 3. Orn S, Cleland JG, Romo M, Kjekshus J, Dickstein K. Recurrent infarction causes the most deaths following myocardial infarction with left ventricular dysfunction. Am J Med 2005;118:752-8.
The Journal of Heart and Lung Transplantation, Vol 32, No 2, February 2013
lung epithelial and mesenchymal cells, it is an infrequent event. Furthermore, it suggests that recipient myofibroblasts are not the predominant proliferating element of bronchiolitis obliterans. From a pathogenetic perspective, our findings show that an alloreactive phenomenon with secondary epithelial injury represents the primary event rather than a primary uncontrolled proliferation of host mesenchymal stem cells at a site of injury. This is in contrast to bone marrow transplant studies showing that injury to and repair of lung parenchyma resulted in colonization of the lung by transdifferentiated hematopoietic stem cells.4,12 There are several possible explanations for the differences between our studies and others. First, selection pressures on transdifferentiated cells in the organ allografts examined may not have been strong enough to illicit the clonal expansion seen in experimental models and in the other studies. These transdifferentiated cells may be abnormal or fragile and have a limited replicative capacity and/or short lifespan. It is possible that these cells were not sampled in 2 of our patients, who were relatively long-term lung transplant survivors (42 years post-transplantation). Local differences and immunosuppression regimens or other treatment policies may interfere with transdifferentiation. Further, transdifferentiation may not be as common as originally described or hypothesized. In conclusion, in this small study we have investigated epithelial and mesenchymal microchimerism in gendermismatched lung allograft recipients. In our experience, there is very limited replacement of donor endothelium and small airway epithelium by recipient stem cells showing transdifferentiation into epithelial and mesenchymal elements. Furthermore, in our experience, the proliferating mesenchymal elements occurring as part of the chronic fibrosing rejection process in bronchiolitis obliterans represent donor myofibroblasts rather than myofibroblasts derived from recipient mesenchymal stem cells.
Disclosure statement The authors have no conflicts of interest to disclose. We thank Diana Winters for secretarial assistance. This study was approved by UPMC IRB # 0411036.
References 1. Suratt BT, Cool CD, Serls AE, et al. Human pulmonary chimerism after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003;168:318-22. 2. Mattsson J, Jansson M, Wernerson A, et al. Lung epithelial cells and type II pneumocytes of donor origin after allogeneic hematopoietic stem cell transplantation. Transplantation 2004;78:154-7. 3. Brocker V, Langer F, Fellous TG, et al. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med 2006;173:1276-82. 4. Kleeberger W, Versmold A, Rothamel T, et al. Increased chimerism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury. Am J Pathol 2003;162:1487-94. 5. Spencer H, Rampling D, Aurora P, et al. Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation. Thorax 2005;60: 60-2.
6. Badri L, Murray S, Liu LX, et al. Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2011;183:1062-70. 7. Borthwick DW, Shahbazian M, Krantz QT, et al. Evidence for stemcell niches in the tracheal epithelium. Am J Respir Cell Mol Biol 2001;24:662-70. 8. Brazelton TR, Shorthouse R, Huang X, et al. Infiltrating recipient mesenchymal cells form the obliterative airway disease lesion and dramatically remodel graft tissue in a model of chronic lung rejection. Transplant Proc 1997;29:2614. 9. Martinu T, Palmer SM, Ortiz LA. Lung-resident mesenchymal stromal cells. A new player in post-transplant bronchiolitis obliterans syndrome? Am J Respir Crit Care Med 2011;183:968-70. 10. Walker N, Badri L, Wettlaufer S, et al. Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts. Am J Pathol 2011;178:2461-9. 11. Kubit V, Sonmez-Alpan E, Zeevi A, et al. Mixed allogeneic chimerism in lung allograft recipients. Hum Pathol 1994;25:408-12. 12. Herzog EL, van Arnam J, Hu B, et al. Threshold of lung injury required for the appearance of marrow-derived lung epithelia. Stem Cells 2006;24:1986-92.
Preponderance and implications of etiologic misclassification in advanced heart failure: A clinical-pathologic investigation Lushna M. Mehra and Patricia A. Uber, BS, Pharm D From the University of Maryland School of Medicine, Baltimore, Maryland
The clinical classification of heart failure that demarcates etiology into ischemic and non-ischemic cardiomyopathy is suggested to guide therapy. Typically, those with an ischemic substrate demonstrate a worse prognosis and are considered candidates for treatment strategies targeted toward modification of the ischemic substrate. Because considerable overlap in these diagnostic strata exists and the extent of clinical misclassification remains uncertain, we sought to review the preponderance and implications of such misclassification by reviewing the final pathologic diagnosis in those hearts available after explantation due to heart transplantation. During a 20-month duration, 112 patients with the clinical etiologic diagnosis of non-ischemic cardiomyopathy (confirmed by a heart failure specialist) underwent heart transplantation at a single center. Patients were excluded if they were aged o 35 years, had congenital or familial heart disease, active myocarditis, peripartum cardiomyopathy, primary valvular heart disease or infiltrative heart disease. The recipient heart was examined histopathologically, and a pathologist blinded to clinical information classified the etiology of heart failure. Ischemic cardiomyopathy was defined as the presence of severe 3-vessel coronary disease (CAD) with myocardial scar. This definition was derived from the analysis of 51 control hearts with ischemic cardiomyopathy confirmed on pathologic analysis. Pathologic analysis of the presence of significant CAD and myocardial ischemia (ante-mortem) was also evaluated. The 112 patients (71% men; aged 57 ⫾ 9 years) in the study had severe ventricular dysfunction (left ventricular ejection fraction, 19% ⫾ 11%) and non-ischemic
Research Correspondence cardiomyopathy as the principle clinical diagnosis at the time of cardiac transplant. Of these, 23 (21%) were reclassified pathologically as ischemic cardiomyopathy. Of the remaining 89 who were accurately classified, 29 (33%) had at least moderate–severe CAD in 4 1 vessel territory, with or without infarction. In addition, 16 explanted hearts (18%) that were appropriately classified were noted to have areas compatible with recent ischemia, as noted by occlusive thrombus or ischemic infarction. The patients with etiologic misclassification were older (59 ⫾ 7 vs 53 ⫾ 8 years, p ¼ 0.001) and had a shorter interval from listing to transplantation (44 vs 58 months, p ¼ 0.05). This investigation suggests a high prevalence of etiologic misclassification in advanced heart failure. The clinical diagnosis of non-ischemic cardiomyopathy typically depends on the presence of a non-ischemic non-invasive evaluation or is established by coronary angiography. Although invasive angiography represents a general gold standard, intravascular ultrasound studies in native and non-native atherosclerosis have demonstrated the relative insensitivity of this approach.1 Diffuse CAD, as noted in patients with diabetes mellitus or in cardiac allograft vasculopathy, are glaring examples of the insensitivity of routine angiography, which greatly underestimates the potential pathologic contribution of concomitant coronary arteriopathy to disease progression and might steer the clinician away from opportunities for therapeutic intervention. Other pathologic studies have alluded to the presence of ischemic events in patients otherwise classified as nonischemic in etiology. Data from 2 clinical trials suggest the hypothesis that coronary thrombosis, which is mostly silent and consequently misdiagnosed, may be considered another potential mechanism, in addition to arrhythmias, that may explain the high rate of sudden death in non-ischemic heart
269 failure.2,3 However, one could argue that anti-platelet, anticoagulation, and lipid-modifying therapy has not been demonstrated to be disease-modifying, and therefore, this misclassification may not have clinical relevance. Conversely, it may be argued that the morbidity that accrues from events that exemplify the progression of heart failure, such as episodes of decompensation, may indeed be modified by the application of anti-ischemic preventative therapy, a concept that may deserve greater exploration in the setting of a large evidence-forming trial. In summary, this clinical-pathologic study has pointed to a high clinical misclassification rate as well as in the direction that ignoring anti-ischemic therapeutic strategies in ‘‘non-ischemic’’ heart failure may be unwise.
Disclosure statement None of the 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.
References 1. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy–2010. J Heart Lung Transplant 2010;29:717-27. 2. Uretsky BF, Thygesen K, Armstrong PW, et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial. Circulation 2000;102:611-6. 3. Orn S, Cleland JG, Romo M, Kjekshus J, Dickstein K. Recurrent infarction causes the most deaths following myocardial infarction with left ventricular dysfunction. Am J Med 2005;118:752-8.