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Can Electron Microscopy of Endomyocardial Biopsies Define Chronic AMR?
S46 Journal of Cardiac Failure Vol. 22 No. 8S August 2016
Cardiovascular Structure/Imaging 117 Regional Myocardial Sympathetic Denervation Precedes Left Ventricular Systolic Dysfunction in Chronic Chagas Cardiomyopathy Leonardo P. Gadioli, Carlos H. Miranda, Alexandre B. Figueiredo, Antonio O. Pintya, Minna D.M. Romano, Benedito C. Maciel, José A. Marin-Neto, Marcus V. Simões; Medical School of Ribeirão Preto—University of Sao Paulo, Ribeirao Preto, Brazil Introduction: Cardiac autonomic denervation is an early and intense disorder in patients with Chronic Chagas Cardiomyopathy (CCC). No previous study has investigated the natural evolution of regional myocardial sympathetic denervation and its correlation with the progression of myocardial dysfunction in the CCC. Purpose: To evaluate in a longitudinal study the presence, extent and progression of regional myocardial sympathetic denervation and its association with the progression of global and segmental left ventricular systolic dysfunction in patients with CCC. Methods: Eighteen patients with CCC underwent assessment of myocardial sympathetic innervation with 123Iodine-metaiodobenzylguanidine-SPECT imaging (MIBG), resting myocardial perfusion scintigraphy with SPECT-99mTc-Sestamibi (MPS), and two-dimensional echocardiography to assess the global systolic function and wall motion abnormalities. After follow-up of 5.4 years, the results of a late evaluation were compared with the baseline results. Results: The mean age at baseline was 55 ± 11 years, mostly men (72%). Between the early and late evaluation, we observed: a significant decrease in left ventricular ejection fraction (56 ± 11 to 49 ± 12%; P = .01), significant increase in the number of segments with akinesia or dyskinesia (from 22 to 34% of the segments), significant increase of the MIBG summed defect score (15 ± 10 to 20 ± 9; P < .01), and a significant increase in the MIBG minus MPS summed score, which estimates the extent of viable, but denervated myocardium, (8.5 ± 10 to 15 ± 7, P < .05). There was a negative correlation between the decrease in left ventricular ejection fraction in late evaluation and the extent of regional myocardial sympathetic denervation at baseline (r = −0.47; P = .03). A multivariate analysis by logistic regression showed that myocardial segments with normal wall motion but exhibiting myocardial sympathetic denervation at baseline had increased chance to develop wall motion abnormalities in the late evaluation (odds ratio = 4.25, P = .001). Additionally, more severe regional myocardial sympathetic denervation was associated with an even greater chance of wall motion deterioration (odds ratio = 11.1; p = 001). Conclusion: The results of this longitudinal study indicate that regional myocardial sympathetic denervation is a progressive derangement in CCC. In addition, the sympathetic denervation is topographically correlated with the forthcoming deterioration of regional wall motion as the disease evolves. These data suggest that sympathetic denervation may be an early marker for disease progression and a potential prognostic tool in patients with CCC.
118 Occult Right Ventricular Cardiotoxicity in Childhood Cancer Survivors Undergoing Antracycline Chemotherapy Vien T. Truong1,2, Komal S. Safdar1, Stephanie Ambach3, Xuexin Gao4, Kan N. Hor5, Joanna Ferranti6, Wojciech Mazur1, Olga Toro-Salazar7; 1The Christ Hospital Health Network, Cincinnati, OH; 2Pham Ngoc Thach University of Medicine, Ho Chi Minh city, Viet Nam; 3College of Allied Health Sciences, The University of Cincinnati, Cincinnati, OH; 4Circle Cardiovascular Imaging Inc, Calgary, AB, Canada; 5Nationwide Children’s Hospital, Columbus, OH; 6Connecticut Children’s Medical Center, Hartford, CT; 7Connecticut Children’s Medical Center, Hartford, CT Introduction: More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing left ventricular (LV) cardiotoxicity. LV strain has been shown to detect myocardial dysfunction in patients with preserved LV systolic function. The purpose of current study was to examine if right ventricular strain is affected in this patient population. Hypothesis: Occult RV dysfunction with antracycline based chemotherapy. Methods: Fifty seven long-term childhood cancer survivors, 10 to 42 years of age, with a cumulative anthracycline dose ≥200 mg/m2 were studied 2.4 to 26.9 years after anthracycline exposure, underwent cardiac magnetic resonance imaging (CMR). The mean value of right ventricular and left ventricular ejection fraction were 57 % and 56%, respectively. RV longitudinal and circumferential strain magnitude was assessed by a dedicated RV tissue tracking software. Results: Fifty one patients with images of sufficient quality were included in the analysis. . Right ventricular EF Z score <-2 was present in 3 (8%) subjects. There was no significant difference in RV global longitudinal and apical circumferential strain magnitude between patients and controls (P > .05 for each). However, there was significant decrease in global, base and mid-cavity circumferential strain magnitude in childhood cancer survivors compared with controls (P < .05 for each). There was no significant correlation with known risk factors of cardiotoxicity and RV strain parameters. RV short axis (SA) basal and medial strain magnitude correlated with global LV longitudinal strain magnitude (ell):−0.43, P = .005, while RV SA medial strain magnitude correlated with RV EF: 0.39 (P = .01). Conclusion: RV circumferential but not longitudinal strain is reduced in childhood cancer survivors undergoing anthracycline chemotherapy. Apical sparing pattern was noted. Further studies are needed to establish clinical significance of this finding.
Right ventricular strain Normal (N = 39) Age (years) 24 (15 to 43)* RV Longitudinal −22.05 ± 3.33 strain (%) RV Circumferential strain (%) Global −11.28 ± 2.13 Basal −10.59 ± 2.09 Mid-cavity −10.70 ± 3.16 Apex −12.54 ± 3.37
Oncology (N = 51)
P
21 ± 6 −22.83 ± 3.88
.09 .32
−10.14 ± 2.24 −9.19 ± 2.43 −8.79 ± 2.93 −12.45 ± 4.03
.02 .005 .004 .91
Continuous variable are expressed as mean ± standard deviation. *Non-normally distributed continuous variables are presented as median (inter-quartile range).
119 Can Electron Microscopy of Endomyocardial Biopsies Define Chronic AMR? Monica Revelo1, Dylan V. Miller2, Josef Stehlik1, Elizabeth Hammond2, Boudi Kfoury2; 1 UUHC, SLC, UT; 2IHC, SLC, UT Background: The 2013 ISHLT classification of antibody-mediated rejection (AMR) does not include histologic criteria for diagnosis of chronic AMR and the lack of specific morphologic lesions of chronic AMR has impaired the understanding and monitoring of this process. However, in kidney transplantation the electron microscopy (EM) findings of transplant glomerulopathy and peritubular capillary lamellation are hallmarks of chronic antibody-mediated injury and define cases with worse outcome. The aim of this study is to describe the EM findings in samples from heart transplanted patients to determine if EM examination might yield insights into the morphology of chronic AMR. Methods: We identified samples from heart transplanted patients with 2 y or more post-transplant that were submitted for EM examination. Reports and electron micrographs were available for review. In each case, scores of ultrastructural features were recorded using a scale of 0–3, where 3 indicated severe changes. Clinical demographic information was also included. Patients with insufficient clinical or pathologic information were excluded. Results: 14 random adult patients with EM studies performed 1989–1994 were identified. Four cases were excluded due to advanced autolysis in the sample. Nine patients were male. Primary heart disease included ischemic cardiomyopathy (7), dilated cardiomyopathy (1) and one with ventricular septal defect. Time from transplant ranged from 2 to 5 years. Four samples were from endomyocardial biopsies and six were from explanted hearts. The EM findings and the histologic diagnosis at the time of examination can be seen in Table 1. Representative images of normal and abnormal basal lamina are shown in Figure. Left panel shows normal perimyocyte capillary; right panel shows changes of lamellation in the basal lamina of the capillary (arrow). All biopsies exhibiting basal lamina lamellation came from recipients who had repetitive episodes of AMR (8–11). Conclusion: Although this is a limited sample, our EM observations suggest that the lamellation of the basal lamina of the perimyocyte capillaries could be used as a marker of chronic AMR and could help to differentiate chronic AMR from other causes of allograft failure. Further EM studies in heart transplant biopsies are warranted. Table 1. Histologic diagnosis and EM findings Type of rejection
Endothelial swelling
Basal lamina lamellation
Fibrosis
AMR (2) ACR (1) Mixed (3) None (4)
2 0 3 2
1 0 2 0
1 1 2 2
Cardiovascular Structure/Imaging 117 Regional Myocardial Sympathetic Denervation Precedes Left Ventricular Systolic Dysfunction in Chronic Chagas Cardiomyopathy Leonardo P. Gadioli, Carlos H. Miranda, Alexandre B. Figueiredo, Antonio O. Pintya, Minna D.M. Romano, Benedito C. Maciel, José A. Marin-Neto, Marcus V. Simões; Medical School of Ribeirão Preto—University of Sao Paulo, Ribeirao Preto, Brazil Introduction: Cardiac autonomic denervation is an early and intense disorder in patients with Chronic Chagas Cardiomyopathy (CCC). No previous study has investigated the natural evolution of regional myocardial sympathetic denervation and its correlation with the progression of myocardial dysfunction in the CCC. Purpose: To evaluate in a longitudinal study the presence, extent and progression of regional myocardial sympathetic denervation and its association with the progression of global and segmental left ventricular systolic dysfunction in patients with CCC. Methods: Eighteen patients with CCC underwent assessment of myocardial sympathetic innervation with 123Iodine-metaiodobenzylguanidine-SPECT imaging (MIBG), resting myocardial perfusion scintigraphy with SPECT-99mTc-Sestamibi (MPS), and two-dimensional echocardiography to assess the global systolic function and wall motion abnormalities. After follow-up of 5.4 years, the results of a late evaluation were compared with the baseline results. Results: The mean age at baseline was 55 ± 11 years, mostly men (72%). Between the early and late evaluation, we observed: a significant decrease in left ventricular ejection fraction (56 ± 11 to 49 ± 12%; P = .01), significant increase in the number of segments with akinesia or dyskinesia (from 22 to 34% of the segments), significant increase of the MIBG summed defect score (15 ± 10 to 20 ± 9; P < .01), and a significant increase in the MIBG minus MPS summed score, which estimates the extent of viable, but denervated myocardium, (8.5 ± 10 to 15 ± 7, P < .05). There was a negative correlation between the decrease in left ventricular ejection fraction in late evaluation and the extent of regional myocardial sympathetic denervation at baseline (r = −0.47; P = .03). A multivariate analysis by logistic regression showed that myocardial segments with normal wall motion but exhibiting myocardial sympathetic denervation at baseline had increased chance to develop wall motion abnormalities in the late evaluation (odds ratio = 4.25, P = .001). Additionally, more severe regional myocardial sympathetic denervation was associated with an even greater chance of wall motion deterioration (odds ratio = 11.1; p = 001). Conclusion: The results of this longitudinal study indicate that regional myocardial sympathetic denervation is a progressive derangement in CCC. In addition, the sympathetic denervation is topographically correlated with the forthcoming deterioration of regional wall motion as the disease evolves. These data suggest that sympathetic denervation may be an early marker for disease progression and a potential prognostic tool in patients with CCC.
118 Occult Right Ventricular Cardiotoxicity in Childhood Cancer Survivors Undergoing Antracycline Chemotherapy Vien T. Truong1,2, Komal S. Safdar1, Stephanie Ambach3, Xuexin Gao4, Kan N. Hor5, Joanna Ferranti6, Wojciech Mazur1, Olga Toro-Salazar7; 1The Christ Hospital Health Network, Cincinnati, OH; 2Pham Ngoc Thach University of Medicine, Ho Chi Minh city, Viet Nam; 3College of Allied Health Sciences, The University of Cincinnati, Cincinnati, OH; 4Circle Cardiovascular Imaging Inc, Calgary, AB, Canada; 5Nationwide Children’s Hospital, Columbus, OH; 6Connecticut Children’s Medical Center, Hartford, CT; 7Connecticut Children’s Medical Center, Hartford, CT Introduction: More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing left ventricular (LV) cardiotoxicity. LV strain has been shown to detect myocardial dysfunction in patients with preserved LV systolic function. The purpose of current study was to examine if right ventricular strain is affected in this patient population. Hypothesis: Occult RV dysfunction with antracycline based chemotherapy. Methods: Fifty seven long-term childhood cancer survivors, 10 to 42 years of age, with a cumulative anthracycline dose ≥200 mg/m2 were studied 2.4 to 26.9 years after anthracycline exposure, underwent cardiac magnetic resonance imaging (CMR). The mean value of right ventricular and left ventricular ejection fraction were 57 % and 56%, respectively. RV longitudinal and circumferential strain magnitude was assessed by a dedicated RV tissue tracking software. Results: Fifty one patients with images of sufficient quality were included in the analysis. . Right ventricular EF Z score <-2 was present in 3 (8%) subjects. There was no significant difference in RV global longitudinal and apical circumferential strain magnitude between patients and controls (P > .05 for each). However, there was significant decrease in global, base and mid-cavity circumferential strain magnitude in childhood cancer survivors compared with controls (P < .05 for each). There was no significant correlation with known risk factors of cardiotoxicity and RV strain parameters. RV short axis (SA) basal and medial strain magnitude correlated with global LV longitudinal strain magnitude (ell):−0.43, P = .005, while RV SA medial strain magnitude correlated with RV EF: 0.39 (P = .01). Conclusion: RV circumferential but not longitudinal strain is reduced in childhood cancer survivors undergoing anthracycline chemotherapy. Apical sparing pattern was noted. Further studies are needed to establish clinical significance of this finding.
Right ventricular strain Normal (N = 39) Age (years) 24 (15 to 43)* RV Longitudinal −22.05 ± 3.33 strain (%) RV Circumferential strain (%) Global −11.28 ± 2.13 Basal −10.59 ± 2.09 Mid-cavity −10.70 ± 3.16 Apex −12.54 ± 3.37
Oncology (N = 51)
P
21 ± 6 −22.83 ± 3.88
.09 .32
−10.14 ± 2.24 −9.19 ± 2.43 −8.79 ± 2.93 −12.45 ± 4.03
.02 .005 .004 .91
Continuous variable are expressed as mean ± standard deviation. *Non-normally distributed continuous variables are presented as median (inter-quartile range).
119 Can Electron Microscopy of Endomyocardial Biopsies Define Chronic AMR? Monica Revelo1, Dylan V. Miller2, Josef Stehlik1, Elizabeth Hammond2, Boudi Kfoury2; 1 UUHC, SLC, UT; 2IHC, SLC, UT Background: The 2013 ISHLT classification of antibody-mediated rejection (AMR) does not include histologic criteria for diagnosis of chronic AMR and the lack of specific morphologic lesions of chronic AMR has impaired the understanding and monitoring of this process. However, in kidney transplantation the electron microscopy (EM) findings of transplant glomerulopathy and peritubular capillary lamellation are hallmarks of chronic antibody-mediated injury and define cases with worse outcome. The aim of this study is to describe the EM findings in samples from heart transplanted patients to determine if EM examination might yield insights into the morphology of chronic AMR. Methods: We identified samples from heart transplanted patients with 2 y or more post-transplant that were submitted for EM examination. Reports and electron micrographs were available for review. In each case, scores of ultrastructural features were recorded using a scale of 0–3, where 3 indicated severe changes. Clinical demographic information was also included. Patients with insufficient clinical or pathologic information were excluded. Results: 14 random adult patients with EM studies performed 1989–1994 were identified. Four cases were excluded due to advanced autolysis in the sample. Nine patients were male. Primary heart disease included ischemic cardiomyopathy (7), dilated cardiomyopathy (1) and one with ventricular septal defect. Time from transplant ranged from 2 to 5 years. Four samples were from endomyocardial biopsies and six were from explanted hearts. The EM findings and the histologic diagnosis at the time of examination can be seen in Table 1. Representative images of normal and abnormal basal lamina are shown in Figure. Left panel shows normal perimyocyte capillary; right panel shows changes of lamellation in the basal lamina of the capillary (arrow). All biopsies exhibiting basal lamina lamellation came from recipients who had repetitive episodes of AMR (8–11). Conclusion: Although this is a limited sample, our EM observations suggest that the lamellation of the basal lamina of the perimyocyte capillaries could be used as a marker of chronic AMR and could help to differentiate chronic AMR from other causes of allograft failure. Further EM studies in heart transplant biopsies are warranted. Table 1. Histologic diagnosis and EM findings Type of rejection
Endothelial swelling
Basal lamina lamellation
Fibrosis
AMR (2) ACR (1) Mixed (3) None (4)
2 0 3 2
1 0 2 0
1 1 2 2