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Microvascular graft vessel disease in children
290
Posters: Cardiovascular Pathology / Pathology - Research and Practice 200 (2004) 289-294
factors were detectable in most tumor cells as well as in adjacent inflammatory cells. The tumors were strongly vascularized comparable to other mesenchymal neoplasms. Conclusions: Our data indicate that myxomas of the heart are well vascularized tumors which differentially express RTKs and their corresponding ligands. VEGFR-2 is strongly present in both endothelial and tumor cells. Since VEGF promotes proliferation via VEGFR-2 tumor growth may be strongly induced via this pathway. VEGFR-1 is also present in this neoplasm and may trigger the proliferative activity of VEGFR-2. In addition, VEGFR-1 should at least in part be responsible for the recruitment of mononuclear cells, such as monocytes. In contrast, c-kit and PDGFR are likely to play a minor role in the development of cardiac myxoma.
'! 3 4
Mierovascular graft vessel disease in children
N. E. HIEMANN, E. WELLNHOFER 1, H. ABDUL-KHALIQ 2, R. HETZER, R. MEYER Deutsches Herzzentrum Berlin, Abt. ftir Herz-, Thorax- und Gef~igchirurgie 1Abt. ftir Kardiologie 2Abt. ftir angeborene Herzfehler
Aims: Atrial fibrosis and selective atrial ischemia promote atrial fibrillation (AF), the most common human arrhythmia causing a substantial increase in morbidity and mortality. Hence, we investigated the expression of hypoxia related genes in AF and correlated hypoxia with cardiac remodeling. Methods: Right atrial appendices (RAA) were collected from 158 patients during cardiac surgery. Using digital image analysis, we quantified cardiac fibrosis, nuclear shape, DNA content, and the densities of CD34- or CD105-positive microvessels. Immunohistochemistry for VEGF, HIFlc~, and KDR were scored and correlated with clinical data as well as the history of AF. Results: Patients with episodes of AF of more than 6 months developed significant interstitial fibrosis of the RAA. Nuclear shape and DNA contents revealed features of an accompanying myocardial hypertrophy and microvessel density increased significantly. These findings were associated with an increased expression of genes involved in hypoxia signaling such as HIFlc~, VEGF, and KDR. Conclusions: Prolonged AF induces cardiac remodeling processes such as myocardial hypertrophy, interstitial fibrosis, and increasing microvessel densitiy. This process is associated with features of hypoxia. It is conceivable that local myocardial hypoxia is of critical importance during cardiac remodeling. Our data support the view that early cardioversion is warranted in AF.
Aims: To test the impact of microvascular graft vessel disease (GVD) on outcome after pediatric heart transplantation (HTx).
Methods: In H&E stainings of 397 right ventricular endomyocardial biopsies (EMB) harvested during the first 10 years after HTx from 130 children (HTx = 118, HLTx = 12, re-Tx = 5; 70 m, 60 f; age at HTx 0-18 years; dCMP = 66, congenital heart disease = 20, others = 44) light microscopic diagnosis of acute cellular rejection (according to ISHLT), the Quilty phenomenon and vascular reaction (morphology of endothelial cells [EC] and blood vessel walls) was performed. Results: The 5 year survival rate was 70%. In 49% of EMB there was evidence of acute cellular rejection. Severe acute cellular rejection was present predominantly during the early postoperative period (<30 days). In 17% of EMB there was evidence of the Quilty phenomenon (7% non-invasive, 10% invasive Quilty). Moderate and severe EC swelling was found in 29.5% and 4% of EMB respectively, evidence of moderate and severe vessel wall thickening in 35.8% and 18.0%. During the observation time there was no change in the number of EMB with moderate EC alterations. The incidence of severe vessel wall thickening increased with time after HTx. Patients with severe vessel wall thickening or severe EC swelling showed decreased survival rates in comparison with patients with moderate or no alterations of the terminal vascular system. In 67% of patients surviving more than 5 years after HTx there was evidence of different grades of microvascular GVD. Conclusions: Microvascular GVD is the most life-threatening long-term complication after pediatric HTx and accounts for one third of cardiac deaths.
1 3 5
Atrial Fibrillation, Fibrosis, and Hypoxia
J. LORENZEN, F. GRAMLEY 2, B. JEDAMZIK, B. RIMANTAS 3, R SCHAUERTE 2, R. AUTSCHBACH 4, K.C. GATTER 1, F. PEZZELLA 1 Institute for Pathology, RWTH-University Hospital Aachen 1Nuffield Department of Cellular Sciences, Oxford University, GB 2Department of Cardiology, RWTH-University Hospital Aachen 3Department of Cardiosurgery, University Hospital Kaunas, LT 4Department of Cardiosurgery, RWTH-University Hospital Aachen
136 Strong Overexpression of NCAM(CD56) is Specific for Human Ischemic Cardiomyopathy and might be Regulated by two novel isoforms of RUNXI(AML1) S. GATTENLOHNER 1, C. WALLER 3, G. ERTL 3, B.-D. B[ILTMANN 2, H.-K. MfOLLER-HERMELINK J A. MARX ~ 1Institut ftir Pathologie, Universit~itWtirzburg, Wtirzburg, Germany 2Institut ftir Pathologie, Universit~it Ttibingen, Ttibingen, Germany 3Medizinische Klinik, Universit~it Wttrzburg, Wtirzburg, Germany
Aims: Chronic myocardial ischemia is the leading cause of impaired myocardial contractility and heart failure. Recently we could show, that NCAM(CD56) is overexpressed in ischemic cardiomyopathy (ICM) compared to normal hearts and is regulated by RUNXI(AML1). The aim of the present study was to investigate the specificity of the NCAM(CD56) overexpression in ICM compared to other heart diseases and to identify the RUNXI(AML1) isoforms that up-/downregulate NCAM(CD56) expression. Methods: RNAse Protection Assay, Western Blot, Immunohistochemiostry, cDNA library construction and radioactive oligonucleotid screening. Results: By RNAse Protection Assay, Western Blot and immunohistochemistry we could show that NCAM(CD56) is not or at most slightly upregulated in heart muscle specimens from patients suffering from congestive cardiomyopathy (n = 8), hypertrophic obstructive cardiomyopathy (n = 2), myocarditis (n = 4) and sarcoidosis (n = 2), whereas strong overexpression of NCAM(CD56) was seen in all biopsies from patients with ICM (n = 14). After construcfion of a heart cDNA library and screening with a 32p radiolabelled oligonucleotide probe specific for RUNX1 we could identify to new isoforms, one of them showing lack of one exon harbouring a transactivation domaine, corresponding to a potential dominant negative isoform. Conclusions: Strong Overexpression of NCAM(CD56) seems to be specific for ICM compared to all other heart diseases investigated as well as normal hearts and might be regulated by 2 new RUNX 1(AML1) isoforms.
Posters: Cardiovascular Pathology / Pathology - Research and Practice 200 (2004) 289-294
factors were detectable in most tumor cells as well as in adjacent inflammatory cells. The tumors were strongly vascularized comparable to other mesenchymal neoplasms. Conclusions: Our data indicate that myxomas of the heart are well vascularized tumors which differentially express RTKs and their corresponding ligands. VEGFR-2 is strongly present in both endothelial and tumor cells. Since VEGF promotes proliferation via VEGFR-2 tumor growth may be strongly induced via this pathway. VEGFR-1 is also present in this neoplasm and may trigger the proliferative activity of VEGFR-2. In addition, VEGFR-1 should at least in part be responsible for the recruitment of mononuclear cells, such as monocytes. In contrast, c-kit and PDGFR are likely to play a minor role in the development of cardiac myxoma.
'! 3 4
Mierovascular graft vessel disease in children
N. E. HIEMANN, E. WELLNHOFER 1, H. ABDUL-KHALIQ 2, R. HETZER, R. MEYER Deutsches Herzzentrum Berlin, Abt. ftir Herz-, Thorax- und Gef~igchirurgie 1Abt. ftir Kardiologie 2Abt. ftir angeborene Herzfehler
Aims: Atrial fibrosis and selective atrial ischemia promote atrial fibrillation (AF), the most common human arrhythmia causing a substantial increase in morbidity and mortality. Hence, we investigated the expression of hypoxia related genes in AF and correlated hypoxia with cardiac remodeling. Methods: Right atrial appendices (RAA) were collected from 158 patients during cardiac surgery. Using digital image analysis, we quantified cardiac fibrosis, nuclear shape, DNA content, and the densities of CD34- or CD105-positive microvessels. Immunohistochemistry for VEGF, HIFlc~, and KDR were scored and correlated with clinical data as well as the history of AF. Results: Patients with episodes of AF of more than 6 months developed significant interstitial fibrosis of the RAA. Nuclear shape and DNA contents revealed features of an accompanying myocardial hypertrophy and microvessel density increased significantly. These findings were associated with an increased expression of genes involved in hypoxia signaling such as HIFlc~, VEGF, and KDR. Conclusions: Prolonged AF induces cardiac remodeling processes such as myocardial hypertrophy, interstitial fibrosis, and increasing microvessel densitiy. This process is associated with features of hypoxia. It is conceivable that local myocardial hypoxia is of critical importance during cardiac remodeling. Our data support the view that early cardioversion is warranted in AF.
Aims: To test the impact of microvascular graft vessel disease (GVD) on outcome after pediatric heart transplantation (HTx).
Methods: In H&E stainings of 397 right ventricular endomyocardial biopsies (EMB) harvested during the first 10 years after HTx from 130 children (HTx = 118, HLTx = 12, re-Tx = 5; 70 m, 60 f; age at HTx 0-18 years; dCMP = 66, congenital heart disease = 20, others = 44) light microscopic diagnosis of acute cellular rejection (according to ISHLT), the Quilty phenomenon and vascular reaction (morphology of endothelial cells [EC] and blood vessel walls) was performed. Results: The 5 year survival rate was 70%. In 49% of EMB there was evidence of acute cellular rejection. Severe acute cellular rejection was present predominantly during the early postoperative period (<30 days). In 17% of EMB there was evidence of the Quilty phenomenon (7% non-invasive, 10% invasive Quilty). Moderate and severe EC swelling was found in 29.5% and 4% of EMB respectively, evidence of moderate and severe vessel wall thickening in 35.8% and 18.0%. During the observation time there was no change in the number of EMB with moderate EC alterations. The incidence of severe vessel wall thickening increased with time after HTx. Patients with severe vessel wall thickening or severe EC swelling showed decreased survival rates in comparison with patients with moderate or no alterations of the terminal vascular system. In 67% of patients surviving more than 5 years after HTx there was evidence of different grades of microvascular GVD. Conclusions: Microvascular GVD is the most life-threatening long-term complication after pediatric HTx and accounts for one third of cardiac deaths.
1 3 5
Atrial Fibrillation, Fibrosis, and Hypoxia
J. LORENZEN, F. GRAMLEY 2, B. JEDAMZIK, B. RIMANTAS 3, R SCHAUERTE 2, R. AUTSCHBACH 4, K.C. GATTER 1, F. PEZZELLA 1 Institute for Pathology, RWTH-University Hospital Aachen 1Nuffield Department of Cellular Sciences, Oxford University, GB 2Department of Cardiology, RWTH-University Hospital Aachen 3Department of Cardiosurgery, University Hospital Kaunas, LT 4Department of Cardiosurgery, RWTH-University Hospital Aachen
136 Strong Overexpression of NCAM(CD56) is Specific for Human Ischemic Cardiomyopathy and might be Regulated by two novel isoforms of RUNXI(AML1) S. GATTENLOHNER 1, C. WALLER 3, G. ERTL 3, B.-D. B[ILTMANN 2, H.-K. MfOLLER-HERMELINK J A. MARX ~ 1Institut ftir Pathologie, Universit~itWtirzburg, Wtirzburg, Germany 2Institut ftir Pathologie, Universit~it Ttibingen, Ttibingen, Germany 3Medizinische Klinik, Universit~it Wttrzburg, Wtirzburg, Germany
Aims: Chronic myocardial ischemia is the leading cause of impaired myocardial contractility and heart failure. Recently we could show, that NCAM(CD56) is overexpressed in ischemic cardiomyopathy (ICM) compared to normal hearts and is regulated by RUNXI(AML1). The aim of the present study was to investigate the specificity of the NCAM(CD56) overexpression in ICM compared to other heart diseases and to identify the RUNXI(AML1) isoforms that up-/downregulate NCAM(CD56) expression. Methods: RNAse Protection Assay, Western Blot, Immunohistochemiostry, cDNA library construction and radioactive oligonucleotid screening. Results: By RNAse Protection Assay, Western Blot and immunohistochemistry we could show that NCAM(CD56) is not or at most slightly upregulated in heart muscle specimens from patients suffering from congestive cardiomyopathy (n = 8), hypertrophic obstructive cardiomyopathy (n = 2), myocarditis (n = 4) and sarcoidosis (n = 2), whereas strong overexpression of NCAM(CD56) was seen in all biopsies from patients with ICM (n = 14). After construcfion of a heart cDNA library and screening with a 32p radiolabelled oligonucleotide probe specific for RUNX1 we could identify to new isoforms, one of them showing lack of one exon harbouring a transactivation domaine, corresponding to a potential dominant negative isoform. Conclusions: Strong Overexpression of NCAM(CD56) seems to be specific for ICM compared to all other heart diseases investigated as well as normal hearts and might be regulated by 2 new RUNX 1(AML1) isoforms.