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Heart Transplant: A Mystery in the Myocardium
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The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
higher thrombin generation than lungs in group 3. Platelet sequestration tended to be lower in surviving lungs when compared to lungs failing within 2h (% of initial platelets remaining at 60’: 61⫾49 vs. 24⫾13, p¼0.057). Conclusions: Results of this analysis demonstrate that intensity of initial coagulation cascade and platelet activation (but not complement activation or anti-non-Gal IgM level) correlates with the outcome of xenogenic lung perfusion. We conclude that targeting coagulation and platelet activation, rather than complement or antibody, are required to improve survival of xenogenic lungs. 358 MAPK/ERK Pathway Activation Leads to Severe Ischemia-ReperfusionInduced Lung Injury M. Okada,1 M. Yamane,1 N. Iga,1 H. Nishikawa,1 S. Yamamoto,1 S. Otani,1 N. Waki,1 S. Hirayama,1 K. Miyoshi,1 S. Sugimoto,1 S. Toyooka,1 T. Oto,1 A. Matsukawa,2 S. Miyoshi.1 1General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Purpose: In the process of ischemia and reperfusion, which may lead to primary graft dysfunction early after lung transplantation, activation of the mitogen-activated protein kinase (MAPK) signaling pathways at a cellular level facilitates cell migration, leading to inflammatory changes and inducing apoptosis. We utilized a mouse model of lung hilar clamping to elucidate ischemia-reperfusion-induced lung injury (IRI) caused by the extracellular signal-regulated kinase (ERK) signaling pathway which is a MAPK pathway. Methods and Materials: Sprouty-related proteins with EVH1 (enabled/ vasodilator-stimulated phosphoprotein homology 1) domain (SPREDs) are known as inhibitors of the MAPK/ERK signaling pathway. U0126 is also an inhibitor of the ERK1/2. We used C57BL/6 wild type mice (WT) and C57BL/6 SPRED2-null mice (KO). Five experimental groups (WT-Sham, WT-IRI, KO-Sham, KO-IRI and KO-IRI þ U0126) were evaluated by using in vivo left hilar clamp model; WT-IRI, KO-IRI and KO-IRI þ U0126 groups underwent 30 minutes of left hilar clamping via median thoracotomy followed by 1 hour of reperfusion. WT-Sham and KO-Sham groups underwent median thoracotomy (n ¼ 5 in each group). Results: Western blotting analysis of IRI mediated activation of MAPKs (ERK, JNK and p38) revealed that the level of phosphorylated ERK was significantly higher in the KO-IRI group (p 0.01). PaO2 which was measured 90 minutes after thoracotomy by sampling oxygenated blood was significantly worse in the KO-IRI group (p o 0.05) and the left lung of the KO-IRI group showed severe edema and hemorrhage with neurtophils infiltration in histological evaluation and FACS analysis (p o 0.05). These severe inflammation was improved in KO-IRI þ U0126 group. Conclusions: Our research showed that the activation of the MAPK/ERK signaling pathway leads to severe ischemia-reperfusion-induced lung injury causing inflammation and edema with infiltration by neutrophils. 359 Heart Transplant: A Mystery in the Myocardium V. Cotarlan, D. Firchau, M. Icardi, J. Goerbig, O. Iqbal, K. LightMcGroary, F. Johnson. Cardiomyopathy Treatment Program, University of Iowa, Iowa City, IA. Introduction: Hypersensitivity myocarditis (HM) is a potentially fatal disease that can lead to refractory heart failure if left untreated. Numerous drugs have been implicated in causing HM. We present a case of HM in a heart transplant recipient treated with Rituximab for post-transplant lymphoproliferative disorder (PTLD). Case Report: A 59 yo man was diagnosed with PTLD 8 months after undergoing heart transplantation. He had an early 2R acute cellular rejection that resolved with increasing baseline immunosuppression that consisted of tacrolimus, Cellcept and prednisone.
An upper endoscopy done for dysphagia, anorexia and weight loss revealed a gastric ulcer and pathology consistent with high grade B cell lymphoma. PET/CT showed cervical, mediastinal, abdominal and pelvic lymphadenopathy as well as hypermetabolic liver and spine lesions consistent with stage IV metastatic disease. Bone marrow biopsy did not show any lymphoma. He was treated with 4 doses of weekly Rituximab and decreased baseline immunosuppression. He was maintained on tacrolimus with a target level around 6 ng/ml and low dose prednisone. He presented one month later with severe heart failure and allograft dysfunction. Heart biopsy showed pericellular and perivascular mixed inflammatory cell infiltrate rich in eosinophils with many degranulating forms suggestive of hypersensitivity myocarditis. There was no evidence of fungal or parasitic infection or heart involvement of the recently diagnosed B cell lymphoma. No eosinophils were seen during the prior cellular rejection. Patient was treated with high dose IV Solu-Medrol and a follow up biopsy one week later showed marked clearing of the eosinophilic infiltrate. Summary: This patient presented with allograft dysfunction after receiving Rituximab, an agent putatively associated with hypersensitivity pneumonitis. Although a complete histologic distinction between HM and acute cellular rejection is not feasible, the features of this infiltrate were more consistent with HM, which was attributed to Rituximab. 360 Mechanical Circulatory Support: When Less Is More D.B. Leviner,1 A. Keidar,2 T. Ben Gal,3 B. Medalion.1 1Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel; 2General Surgery B, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel; 3Cardiology, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel. Introduction: We present a case of a morbidly obese patient who underwent LVAD implantation, and subsequently laparoscopic sleeve gastrectomy and explantation of the LVAD following improvement in her cardiac function. Case Report: A 44 year old female with BMI of 40 and dilated cardiomyopathy presented with deterioration of her CHF. She was considered high risk for transplantation, and underwent an uneventful LVAD implantation. During follow-up her condition improved but she continued to gain weight and later started to experience functional deterioration that was attributed to her obesity. Her BMI at that time was 45. A cardiac CT demonstrated a malpositioned inflow cannula directed toward the free wall of the LV by a raised diaphragm. Her attempts to lose weight were futile and thirteen months after the LVAD implantation she underwent an uneventful laparoscopic sleeve gastrectomy. In the next 6 weeks she lost 17 Kg. She presented back to our hospital when her LVAD monitor displayed a malfunction alarm. During this time she was hemodynamically stable. An echocardiogram revealed no flow in the LVAD, but demonstrated a significant improvement of the global function of the left ventricle with an EF of 40%. Several days later her LVAD was explanted. Eleven months later, she lost 40 Kg with a BMI of 29 and she is symptom free.
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
higher thrombin generation than lungs in group 3. Platelet sequestration tended to be lower in surviving lungs when compared to lungs failing within 2h (% of initial platelets remaining at 60’: 61⫾49 vs. 24⫾13, p¼0.057). Conclusions: Results of this analysis demonstrate that intensity of initial coagulation cascade and platelet activation (but not complement activation or anti-non-Gal IgM level) correlates with the outcome of xenogenic lung perfusion. We conclude that targeting coagulation and platelet activation, rather than complement or antibody, are required to improve survival of xenogenic lungs. 358 MAPK/ERK Pathway Activation Leads to Severe Ischemia-ReperfusionInduced Lung Injury M. Okada,1 M. Yamane,1 N. Iga,1 H. Nishikawa,1 S. Yamamoto,1 S. Otani,1 N. Waki,1 S. Hirayama,1 K. Miyoshi,1 S. Sugimoto,1 S. Toyooka,1 T. Oto,1 A. Matsukawa,2 S. Miyoshi.1 1General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Purpose: In the process of ischemia and reperfusion, which may lead to primary graft dysfunction early after lung transplantation, activation of the mitogen-activated protein kinase (MAPK) signaling pathways at a cellular level facilitates cell migration, leading to inflammatory changes and inducing apoptosis. We utilized a mouse model of lung hilar clamping to elucidate ischemia-reperfusion-induced lung injury (IRI) caused by the extracellular signal-regulated kinase (ERK) signaling pathway which is a MAPK pathway. Methods and Materials: Sprouty-related proteins with EVH1 (enabled/ vasodilator-stimulated phosphoprotein homology 1) domain (SPREDs) are known as inhibitors of the MAPK/ERK signaling pathway. U0126 is also an inhibitor of the ERK1/2. We used C57BL/6 wild type mice (WT) and C57BL/6 SPRED2-null mice (KO). Five experimental groups (WT-Sham, WT-IRI, KO-Sham, KO-IRI and KO-IRI þ U0126) were evaluated by using in vivo left hilar clamp model; WT-IRI, KO-IRI and KO-IRI þ U0126 groups underwent 30 minutes of left hilar clamping via median thoracotomy followed by 1 hour of reperfusion. WT-Sham and KO-Sham groups underwent median thoracotomy (n ¼ 5 in each group). Results: Western blotting analysis of IRI mediated activation of MAPKs (ERK, JNK and p38) revealed that the level of phosphorylated ERK was significantly higher in the KO-IRI group (p 0.01). PaO2 which was measured 90 minutes after thoracotomy by sampling oxygenated blood was significantly worse in the KO-IRI group (p o 0.05) and the left lung of the KO-IRI group showed severe edema and hemorrhage with neurtophils infiltration in histological evaluation and FACS analysis (p o 0.05). These severe inflammation was improved in KO-IRI þ U0126 group. Conclusions: Our research showed that the activation of the MAPK/ERK signaling pathway leads to severe ischemia-reperfusion-induced lung injury causing inflammation and edema with infiltration by neutrophils. 359 Heart Transplant: A Mystery in the Myocardium V. Cotarlan, D. Firchau, M. Icardi, J. Goerbig, O. Iqbal, K. LightMcGroary, F. Johnson. Cardiomyopathy Treatment Program, University of Iowa, Iowa City, IA. Introduction: Hypersensitivity myocarditis (HM) is a potentially fatal disease that can lead to refractory heart failure if left untreated. Numerous drugs have been implicated in causing HM. We present a case of HM in a heart transplant recipient treated with Rituximab for post-transplant lymphoproliferative disorder (PTLD). Case Report: A 59 yo man was diagnosed with PTLD 8 months after undergoing heart transplantation. He had an early 2R acute cellular rejection that resolved with increasing baseline immunosuppression that consisted of tacrolimus, Cellcept and prednisone.
An upper endoscopy done for dysphagia, anorexia and weight loss revealed a gastric ulcer and pathology consistent with high grade B cell lymphoma. PET/CT showed cervical, mediastinal, abdominal and pelvic lymphadenopathy as well as hypermetabolic liver and spine lesions consistent with stage IV metastatic disease. Bone marrow biopsy did not show any lymphoma. He was treated with 4 doses of weekly Rituximab and decreased baseline immunosuppression. He was maintained on tacrolimus with a target level around 6 ng/ml and low dose prednisone. He presented one month later with severe heart failure and allograft dysfunction. Heart biopsy showed pericellular and perivascular mixed inflammatory cell infiltrate rich in eosinophils with many degranulating forms suggestive of hypersensitivity myocarditis. There was no evidence of fungal or parasitic infection or heart involvement of the recently diagnosed B cell lymphoma. No eosinophils were seen during the prior cellular rejection. Patient was treated with high dose IV Solu-Medrol and a follow up biopsy one week later showed marked clearing of the eosinophilic infiltrate. Summary: This patient presented with allograft dysfunction after receiving Rituximab, an agent putatively associated with hypersensitivity pneumonitis. Although a complete histologic distinction between HM and acute cellular rejection is not feasible, the features of this infiltrate were more consistent with HM, which was attributed to Rituximab. 360 Mechanical Circulatory Support: When Less Is More D.B. Leviner,1 A. Keidar,2 T. Ben Gal,3 B. Medalion.1 1Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel; 2General Surgery B, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel; 3Cardiology, Rabin Medical Center, Beilinson Campus, Petach Tiqva, Israel. Introduction: We present a case of a morbidly obese patient who underwent LVAD implantation, and subsequently laparoscopic sleeve gastrectomy and explantation of the LVAD following improvement in her cardiac function. Case Report: A 44 year old female with BMI of 40 and dilated cardiomyopathy presented with deterioration of her CHF. She was considered high risk for transplantation, and underwent an uneventful LVAD implantation. During follow-up her condition improved but she continued to gain weight and later started to experience functional deterioration that was attributed to her obesity. Her BMI at that time was 45. A cardiac CT demonstrated a malpositioned inflow cannula directed toward the free wall of the LV by a raised diaphragm. Her attempts to lose weight were futile and thirteen months after the LVAD implantation she underwent an uneventful laparoscopic sleeve gastrectomy. In the next 6 weeks she lost 17 Kg. She presented back to our hospital when her LVAD monitor displayed a malfunction alarm. During this time she was hemodynamically stable. An echocardiogram revealed no flow in the LVAD, but demonstrated a significant improvement of the global function of the left ventricle with an EF of 40%. Several days later her LVAD was explanted. Eleven months later, she lost 40 Kg with a BMI of 29 and she is symptom free.