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Antithymocyte Globulin Therapy for Chronic Lung Allograft Dysfunction Following Lung Transplantation
S312
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
gradient of ET-1 levels across the lung was significantly higher in patients with pulmonary venous hypertension compared to those without (p = 0.005). However presence of pulmonary venous hypertension did not significantly affect the levels of BET-1 ; neither in venous, arterial blood nor the BET-1 gradient across the lung. Conclusion: Patients with HFnEF have an elevated level of ET-1 in peripheral venous blood, arterial blood as well as an elevated ET-1 gradient across the lung. The level of ET-1 is further amplified by the presence of pulmonary venous hypertension. 8( 65) Soluble Vascular Endothelial Growth Factor Receptor -1 (sFlt-1) Is Decreased in Patients With Pulmonary Arterial Hypertension N. Selimovic ,1 F. Khaliel,1 L. Mattsson Hulten.2 1Heart Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; 2Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. Purpose: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis and vascular remodeling in patients with pulmonary arterial hypertension (PAH). VEGF acts via two different receptors: KDR and Flt-1. Flt-1 exists both in membrane -fixed and soluble forms. The soluble form is perhaps the only known natural direct antagonist of VEGF and may have a role in anti-angiogenesis therapy. The purpose of our study was to assess the level of sFlt-1 and VEGF in PAH patients and compare with controls. Methods: Blood samples were obtained simultaneously from the radial artery (RA) and the pulmonary artery (PA) in patients with PAH (n= 27) and CTEPH (n= 7) during right heart catheterization. The control group included patients with WPW syndrome (n= 20), otherwise healthy. The levels of VEGF and sFlt-1 were estimated by enzyme-linked immunosorbent assay. Results: We found significantly higher level of VEGF in patients with PAH in both RA and PA than controls (758±608 vs. 203±102 pg/ml, p< 0.001 and 440±308 vs. 212±111 pg/ml, p= 0.002, respectively) and at the same time significantly lower level of sFlt-1in patients than in controls (3335±4828 vs. 12716±10015 pg/ml, p< 0.001 and 2289±3204 vs. 13556±12141, p< 0.001 respectively. Analysis showed significantly negative correlation between VEGF and sFlt-1 (R= -0.48 with p< 0.001). Conclusion: These data have raised a question if we can reverse or stop the progress of vascular remodeling in PAH patients by addition of excess sFlt-1 or by removal of VEGF. 8( 66) Surgical Treatment of Chronic Thromboembolic Pulmonary Hypertension: from Transplantation to Endarterectomy A.M. D’Armini ,1 M. Morsolini,1 G. Mattiucci,1 V. Grazioli,1 M. Pin,1 A. Valentini,2 C. Goggi,1 R. Dore.2 1Cardiac Surgery, University of Pavia School of Medicine, Foundation I.R.C.C.S. San Matteo Hospital, Pavia, Italy; 2Radiology, University of Pavia School of Medicine, Foundation I.R.C.C.S. San Matteo Hospital, Pavia, Italy. Purpose: The most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). The pivotal decision is to identify patients with accessible lesions in whom PEA is expected to be effective. The fine line between operable and inoperable CTEPH is variable, according to the surgeon’s experience. The aim of our report is to describe the changes occurred during our 23-year experience in the surgical treatment of CTEPH. Methods: The first surgical treatment of CTEPH was heart-lung transplantation (Tx) in 1991. The PEA program started in 1994, and 522 PEAs were performed to date. Since 1995, given the evidence of right ventricular remodelling following PEA, the procedure of choice for patients not amenable of PEA has changed from heart-lung to double-lung Tx. In 2003, PEA was performed in a patient previously deemed as inoperable and listed for Tx. From 2004 onward, we reviewed our Tx list to reassess CTEPH operability. Results: Patient referrals increased substantially over the years, and we became more confident with PEA. This resulted in a significant increase in PEAs performed, currently more than 300 in the past 5 years. Thus, operability rate increased from 74% (year 2004) to 90% (year 2012). In parallel, the number of Tx decreased significantly, being 16 Tx from 1991 to 2005 and 3 Tx from 2006 onward, including rescue Tx following failure of PEA.
Conclusion: PEA is an elective surgery, non donor-dependent, and age is not a contraindication for surgery. There is no degree of hemodynamic or functional impairment which contraindicate PEA, which is indicated even in mildly symptomatic patients (WHO functional class II). PEA also is not followed by the typical complications described for Tx, as graft rejection and immunologic and infective complications. Outcome after PEA is excellent in terms of hemodynamic recovery, quality of life with steady functional improvement, and long-term survival (75% at 20 years). Hence, CTEPH patients should be referred early to Centres experienced in both PEA and Tx, to offer the best treatment and to achieve the best results. This strategy maximizes the use of scarce donor organs by offering a conservative surgery for CTEPH patients. 8( 67) Antithymocyte Globulin Therapy for Chronic Lung Allograft Dysfunction Following Lung Transplantation E. George , S. Ivulich, M. Paraskeva, B. Levvey, G. Snell, G.P. Westall. Lung Transplant Service, Alfred Hospital, Melbourne, Australia. Purpose: Chronic lung allograft syndrome (CLAD) is the major cause of late morbidity and mortality after lung transplantation (LTx). Despite some early positive studies, the role of horse antithymocyte globulin (ATG) in arresting the course of CLAD remains unclear. Methods: A retrospective single-center case-review of LTx recipients who received ATG (5 day course, 500mg iv od, subsequent dose aiming to suppress CD2 counts < 10%) as second line therapy for CLAD, following initial treatment with pulsed methylprednisolone. Since 2002, and from a total cohort of 998 LTx recipients, we identified 53 patients (male, n = 30, mean age 47 +/- 16 yrs) with declining lung function who received ATG at a mean of 1082 +/- 862 days post LTx. Subsequent follow-up was 833 +/- 889 days (range, 66 to 3511 days). Rate of decline of FEV1 before and after ATG therapy was assessed as a marker of efficacy. Results: ATG therapy was generally well tolerated with few side effects. ATG therapy was associated with a favourable response in 26/53 patients (stable FEV1, n = 17, reduced decline of FEV1, n = 9). Therapy had no impact on CLAD progression in 27/53 patients, with death (n = 21) or re-LTx (n = 4) resulting at 438 +/- 581 days post-ATG therapy. Neither CLAD stage, percentage decrease in peripheral blood lymphocyte count, gender, age nor underlying diagnosis predicted a response to therapy. Conclusion: ATG therapy alters the FEV1 decline in a significant proportion of LTx patients. Prospective randomised placebo-controlled studies are needed to confirm this benefit. 8( 68) Assessment of Medication Regimen Complexity Over Time Following Heart Transplantation B.M. Bryant ,1 A.M. Libby,2 K. Metz,2 R.L. Page,2 J.A. Lindenfeld,3 C.L. Aquilante.1 1Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO; 2Department of Clinical Pharmacy, University of Colorado, Aurora, CO; 3Division of Cardiology, University of Colorado, Aurora, CO. Purpose: Medication regimen complexity includes many characteristics of a patient’s drug regimen, beyond just number of medications. The Medication Regimen Complexity Index (MRCI) is a validated instrument that accounts for drug dosage forms, frequencies, and additional directions. The objective of this study was to quantify medication regimen complexity over time in heart transplant (HTx) patients using the MRCI tool. Methods: HTx patient medication lists were abstracted from the medical record at transplant (Tx) discharge, and years 1, 3, and 5 post-Tx. Medications were separated into 3 types: Tx, Other prescriptions (Other Rx), and OTC. Medications were counted and dosage forms, frequencies, and additional directions were scored using the MRCI tool. A total MRCI score was calculated for each patient, along with scores for each medication type. Data were compared over time using repeated measures ANOVA, with age at time of Tx as a covariate. Results: The study included n= 60 HTx patients (75% men; Tx dates= 19972008; mean age at Tx= 50 ± 13 years). MRCI scores and medication counts (mean ± SD) are shown in the table. Mean total MRCI score (37.2 +/- 9.6)
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2014
gradient of ET-1 levels across the lung was significantly higher in patients with pulmonary venous hypertension compared to those without (p = 0.005). However presence of pulmonary venous hypertension did not significantly affect the levels of BET-1 ; neither in venous, arterial blood nor the BET-1 gradient across the lung. Conclusion: Patients with HFnEF have an elevated level of ET-1 in peripheral venous blood, arterial blood as well as an elevated ET-1 gradient across the lung. The level of ET-1 is further amplified by the presence of pulmonary venous hypertension. 8( 65) Soluble Vascular Endothelial Growth Factor Receptor -1 (sFlt-1) Is Decreased in Patients With Pulmonary Arterial Hypertension N. Selimovic ,1 F. Khaliel,1 L. Mattsson Hulten.2 1Heart Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; 2Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. Purpose: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis and vascular remodeling in patients with pulmonary arterial hypertension (PAH). VEGF acts via two different receptors: KDR and Flt-1. Flt-1 exists both in membrane -fixed and soluble forms. The soluble form is perhaps the only known natural direct antagonist of VEGF and may have a role in anti-angiogenesis therapy. The purpose of our study was to assess the level of sFlt-1 and VEGF in PAH patients and compare with controls. Methods: Blood samples were obtained simultaneously from the radial artery (RA) and the pulmonary artery (PA) in patients with PAH (n= 27) and CTEPH (n= 7) during right heart catheterization. The control group included patients with WPW syndrome (n= 20), otherwise healthy. The levels of VEGF and sFlt-1 were estimated by enzyme-linked immunosorbent assay. Results: We found significantly higher level of VEGF in patients with PAH in both RA and PA than controls (758±608 vs. 203±102 pg/ml, p< 0.001 and 440±308 vs. 212±111 pg/ml, p= 0.002, respectively) and at the same time significantly lower level of sFlt-1in patients than in controls (3335±4828 vs. 12716±10015 pg/ml, p< 0.001 and 2289±3204 vs. 13556±12141, p< 0.001 respectively. Analysis showed significantly negative correlation between VEGF and sFlt-1 (R= -0.48 with p< 0.001). Conclusion: These data have raised a question if we can reverse or stop the progress of vascular remodeling in PAH patients by addition of excess sFlt-1 or by removal of VEGF. 8( 66) Surgical Treatment of Chronic Thromboembolic Pulmonary Hypertension: from Transplantation to Endarterectomy A.M. D’Armini ,1 M. Morsolini,1 G. Mattiucci,1 V. Grazioli,1 M. Pin,1 A. Valentini,2 C. Goggi,1 R. Dore.2 1Cardiac Surgery, University of Pavia School of Medicine, Foundation I.R.C.C.S. San Matteo Hospital, Pavia, Italy; 2Radiology, University of Pavia School of Medicine, Foundation I.R.C.C.S. San Matteo Hospital, Pavia, Italy. Purpose: The most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). The pivotal decision is to identify patients with accessible lesions in whom PEA is expected to be effective. The fine line between operable and inoperable CTEPH is variable, according to the surgeon’s experience. The aim of our report is to describe the changes occurred during our 23-year experience in the surgical treatment of CTEPH. Methods: The first surgical treatment of CTEPH was heart-lung transplantation (Tx) in 1991. The PEA program started in 1994, and 522 PEAs were performed to date. Since 1995, given the evidence of right ventricular remodelling following PEA, the procedure of choice for patients not amenable of PEA has changed from heart-lung to double-lung Tx. In 2003, PEA was performed in a patient previously deemed as inoperable and listed for Tx. From 2004 onward, we reviewed our Tx list to reassess CTEPH operability. Results: Patient referrals increased substantially over the years, and we became more confident with PEA. This resulted in a significant increase in PEAs performed, currently more than 300 in the past 5 years. Thus, operability rate increased from 74% (year 2004) to 90% (year 2012). In parallel, the number of Tx decreased significantly, being 16 Tx from 1991 to 2005 and 3 Tx from 2006 onward, including rescue Tx following failure of PEA.
Conclusion: PEA is an elective surgery, non donor-dependent, and age is not a contraindication for surgery. There is no degree of hemodynamic or functional impairment which contraindicate PEA, which is indicated even in mildly symptomatic patients (WHO functional class II). PEA also is not followed by the typical complications described for Tx, as graft rejection and immunologic and infective complications. Outcome after PEA is excellent in terms of hemodynamic recovery, quality of life with steady functional improvement, and long-term survival (75% at 20 years). Hence, CTEPH patients should be referred early to Centres experienced in both PEA and Tx, to offer the best treatment and to achieve the best results. This strategy maximizes the use of scarce donor organs by offering a conservative surgery for CTEPH patients. 8( 67) Antithymocyte Globulin Therapy for Chronic Lung Allograft Dysfunction Following Lung Transplantation E. George , S. Ivulich, M. Paraskeva, B. Levvey, G. Snell, G.P. Westall. Lung Transplant Service, Alfred Hospital, Melbourne, Australia. Purpose: Chronic lung allograft syndrome (CLAD) is the major cause of late morbidity and mortality after lung transplantation (LTx). Despite some early positive studies, the role of horse antithymocyte globulin (ATG) in arresting the course of CLAD remains unclear. Methods: A retrospective single-center case-review of LTx recipients who received ATG (5 day course, 500mg iv od, subsequent dose aiming to suppress CD2 counts < 10%) as second line therapy for CLAD, following initial treatment with pulsed methylprednisolone. Since 2002, and from a total cohort of 998 LTx recipients, we identified 53 patients (male, n = 30, mean age 47 +/- 16 yrs) with declining lung function who received ATG at a mean of 1082 +/- 862 days post LTx. Subsequent follow-up was 833 +/- 889 days (range, 66 to 3511 days). Rate of decline of FEV1 before and after ATG therapy was assessed as a marker of efficacy. Results: ATG therapy was generally well tolerated with few side effects. ATG therapy was associated with a favourable response in 26/53 patients (stable FEV1, n = 17, reduced decline of FEV1, n = 9). Therapy had no impact on CLAD progression in 27/53 patients, with death (n = 21) or re-LTx (n = 4) resulting at 438 +/- 581 days post-ATG therapy. Neither CLAD stage, percentage decrease in peripheral blood lymphocyte count, gender, age nor underlying diagnosis predicted a response to therapy. Conclusion: ATG therapy alters the FEV1 decline in a significant proportion of LTx patients. Prospective randomised placebo-controlled studies are needed to confirm this benefit. 8( 68) Assessment of Medication Regimen Complexity Over Time Following Heart Transplantation B.M. Bryant ,1 A.M. Libby,2 K. Metz,2 R.L. Page,2 J.A. Lindenfeld,3 C.L. Aquilante.1 1Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO; 2Department of Clinical Pharmacy, University of Colorado, Aurora, CO; 3Division of Cardiology, University of Colorado, Aurora, CO. Purpose: Medication regimen complexity includes many characteristics of a patient’s drug regimen, beyond just number of medications. The Medication Regimen Complexity Index (MRCI) is a validated instrument that accounts for drug dosage forms, frequencies, and additional directions. The objective of this study was to quantify medication regimen complexity over time in heart transplant (HTx) patients using the MRCI tool. Methods: HTx patient medication lists were abstracted from the medical record at transplant (Tx) discharge, and years 1, 3, and 5 post-Tx. Medications were separated into 3 types: Tx, Other prescriptions (Other Rx), and OTC. Medications were counted and dosage forms, frequencies, and additional directions were scored using the MRCI tool. A total MRCI score was calculated for each patient, along with scores for each medication type. Data were compared over time using repeated measures ANOVA, with age at time of Tx as a covariate. Results: The study included n= 60 HTx patients (75% men; Tx dates= 19972008; mean age at Tx= 50 ± 13 years). MRCI scores and medication counts (mean ± SD) are shown in the table. Mean total MRCI score (37.2 +/- 9.6)