Made available in DSpace on 2014-12-17T14:13:45Z (GMT). No. of bitstreams: 1 CarlosDMO_DISSERT.pdf: 3393165 bytes, checksum: 8775fe07131b0869171353c32e39624c (MD5) Previous issue date: 2009-11-27 / Heart transplantation (HT) represents one of the greatest advances in medicine over the last decades. It is indicated for patients with severe heart disease unresponsive to clinical treatment and conventional surgery, poor short-term prognosis and a 1- year mortality rate over 40%. HT has improved survival worldwide (80% in the first year, 70% in five years and 60% in ten years). However, the procedure has been associated with weight change and increased risk of secondary conditions such as diabetes, hypertension, dyslipidemia and obesity due to immunosuppressive therapy following transplantation. The objective of this study was to determine the impact of weight change on the metabolic stability of HT patients. The study was retrospective with data collected from the records of 82 adult patients (83% male; average age 45.06?12.04 years) submitted to HT between October 1997 and December 2005 at a transplantation service in Cear? (Brazil). The selected outcome variables (biopathological profile, weight and body mass index&#8213;BMI) were related to biochemical and metabolic change. The results were expressed in terms of frequency, measures of central tendency, Student s t test and Pearson s correlation coefficients. The analysis showed that following HT the average global BMI increased from 23.77?3.68kg/m2 to 25.48?3.92kg/m2 in the first year and to 28.38?4.97kg/m2 in the fifth. Overweight/obese patients (BMI &#8805; 25 kg/m2) had higher average levels of glucose, total cholesterol, low-density lipoprotein and triglycerides than patients with eutrophy/malnutrition (BMI < 25 kg/m2). In conclusion, overweight/obese patients were likely to present higher average levels of glucose, triglycerides, total cholesterol and fractions than patients with eutrophy/malnutrition, indicating a direct and significant relation between nutritional status and weight change in the metabolic profile of HT patients / O Transplante Card?aco (TC) tornou-se um dos grandes avan?os da medicina nas ?ltimas d?cadas. ? um procedimento indicado para pacientes com doen?a card?aca avan?ada, refrat?ria ao tratamento cl?nico e cir?rgico convencional, progn?stico reservado em curto prazo e mortalidade acima de 40% no prazo de um ano na evolu??o natural da doen?a. Em todo o mundo seus resultados t?m evidenciado melhora significante na sobrevida, sendo considerada de 80% no primeiro ano, 70% em cinco anos e 60% em dez anos. No entanto, as altera??es de peso ap?s o procedimento frequentemente ocorrem e aumentam os riscos de doen?as secund?rias como diabetes, hipertens?o, dislipidemia e obesidade, complica??es que est?o associadas ? terapia imunossupressora indispens?vel ap?s o TC. O objetivo deste estudo foi determinar o impacto da variabilidade de peso na estabilidade metab?lica de pacientes transplantados do cora??o. O desenho do estudo foi do tipo retrospectivo documental, realizado com 82 pacientes adultos submetidos ao TC entre outubro de 1997 a dezembro de 2005 em centro transplantador no Cear?, sendo 83% do sexo masculino e 17% do sexo feminino com idade m?dia de 45,06?12,04 anos. As vari?veis estudadas foram o perfil biopatol?gico, o peso e o ?ndice de massa corporal (IMC), relacionadas ?s altera??es bioqu?micas-metab?licas. Os dados foram descritos usando frequ?ncias, medidas de tend?ncia central, teste t de Student e coeficiente de correla??o de Pearson. Ap?s a an?lise dos dados, verificou-se que a m?dia global do IMC aumentou de 23,77?3,68 kg/m2 antes do TC, para 25,48?3,92 kg/m2 no primeiro ano e para 28,38?4,97 kg/m2 no quinto. Os pacientes com sobrepeso/ obesidade (IMC &#8805;25 kg/m2) apresentaram valores m?dios de glicose, colesterol total, lipoprote?na de baixa XIV densidade (LDL) e triglic?rides maiores que os pacientes com eutrofia/ desnutri??o (IMC < 25 kg/m2). Diante dos resultados encontrados nesse estudo, conclui-se que os pacientes com sobrepeso/ obesidade est?o propensos a apresentar n?veis de glicose, colesterol total, LDL e triglic?rides mais elevados que os pacientes com eutrofia/ desnutri??o, o que demonstra que houve uma rela??o direta e significativa entre o estado nutricional e a variabilidade de peso no perfil metab?lico de pacientes transplantados card?acos

A resposta imune dirigida a autoantígenos pode contribuir para a patogênese das doenças autoimunes. Porém, também é discutido o papel imunorregulador da autoimunidade em processos inflamatórios e na rejeição do aloenxerto. Nós pesquisamos os autoanticorpos IgG e IgM reativos a peptídeos da miosina cardíaca (MC) e da proteína de choque térmico 60 (Hsp60) no soro de indivíduos sadios (IS, n=30; 3 momentos com intervalos de 6 meses) e indivíduos transplantados cardíacos (Tx, n=65, > 2 amostras/indivíduo, de diferentes períodos Tx: pré-Tx, T1: < 1 ano, T2: 1 a 5 anos e T3: >5 anos), por ensaio imunoenzimático (ELISA). Todos os sujeitos do estudo tiveram anticorpos IgG ou IgM que reconheceram pelo menos um dos peptídeos avaliados. Os anticorpos IgG de indivíduos Tx reconheceram mais peptídeos do que dos IS, para a MC (12,2 ± 8,5, intervalo: 132 peptídeos versus 5,2 ± 3,0, intervalo: 0-14; p<0,0001), e para a Hsp60 (6,0 ± 4,4, intervalo: 0-18 versus 3,9 ± 3,0, intervalo: 0-12; p=0,0208). A frequência de indivíduos positivos para os anticorpos IgG foi maior no grupo Tx do que nos sadio (p<0,05), com reatividade para a maioria dos peptídeos da MC e da Hsp60. Em contraste, a frequência de indivíduos positivos para os anticorpos IgM foi maior no grupo de IS do que no Tx (p<0,05), principalmente para a reatividade dirigida aos peptídeos da MC. Os indivíduos do grupo Tx reconheceram todos os peptídeos da MC, inclusive alguns não reconhecidos pelos sadios (S2: 19, 21, 22, 25, 27, e 29). A variabilidade temporal da autoimunidade humoral aos peptídeos desses antígenos foi maior no grupo Tx (p<0,001), indicando maior estabilidade do perfil no estado fisiológico. No grupo Tx, a frequência de indivíduos positivos para anticorpos IgG e o número de peptídeos reconhecidos foram maiores nos períodos de pré- Tx e T1 e na rejeição (p<0,05). Em contraste, para os anticorpos IgM, a frequência de indivíduos positivos e número de peptídeos reconhecidos foram maiores nos períodos de T1, T2 e no momento sem rejeição (p<0,05). Em resumo, no estado fisiológico, observamos um predomínio de autoanticorpos dirigidos à MC e à Hsp60 do tipo IgM, enquanto que no período pré-Tx e durante a rejeição o predomínio foi de IgG. Com base nesses resultados, interpretamos que o ambiente inflamatório da doença cardíaca e da rejeição possa induzir uma maior expressão de Hsp60 e exposição da MC - decorrente da necrose de cardiomiócitos - a células do sistema imune. A resposta imune desencadeada, neste contexto, culminaria na mudança do isotipo IgM, predominante no estado fisiológico, para o isotipo IgG, predominante no quadro de inflamação. Em conclusão, identificamos um perfil distinto da autoimunidade humoral dirigida à miosina cardíaca e à Hsp60, no estado fisiológico e no transplante cardíaco. Novos estudos permitirão avaliar a atividade funcional desses autoanticorpos no enxerto e nas células do sistema imune, talvez desempenhando um papel na rejeição ou na manutenção da homeostase, no contexto fisiológico / The immune response directed to self antigens can contribute to the pathogenesis of autoimmune diseases. However, autoimmunity may also have an immunoregulatory role in allograft rejection and in other inflammatory processes. We analyzed IgG and IgM autoantibodies reactive to peptides from the human cardiac myosin (CM) and the heat shock protein 60 (Hsp60) in the sera of healthy individuals (HI, n=30, 3 time points with 6 month intervals) and heart transplant individuals (Tx, n=65, >2 samples/individual, from different Tx periods: pre-Tx, T1: <1 year post-Tx, T2: 1 to 5 years and T3: >5 years), by Enzyme-Linked Immunosorbent Assay (ELISA). All subjects from both groups had IgG or IgM antibodies that recognized at least one of peptides studied. The numbers of peptides recognized by IgG antibodies was higher in the Tx group than in the HI, for CM (12.2 ± 8.5, range: 132 peptides versus 5.2 ± 3.0, range: 014 peptides; p <0.0001) and for Hsp60 (6.0 ± 4.4, range: 0-18 peptides versus 3.9 ± 3.0, range: 012 peptides; p=0.0208). The frequency of individuals displaying IgG antibodies was higher in the Tx group than in HI (p<0.05), for both CM and Hsp60. In contrast, the frequency of individuals with IgM antibodies was higher in HI than in the Tx group (p<0.05), mainly for CM. The Tx individuals recognized all CM peptides, including those not recognized by healthy individuals (S2: 19, 21, 22, 25, 27, e 29). Time variability of humoral autoimmunity directed to peptides of both antigens was higher in the Tx group (p<0,001), indicating a more stable profile in the physiologic state. In the Tx group, the frequency of individuals with IgG autoantibodies and the number of peptides recognized were higher in the pre-Tx and T1 periods and during rejection (p<0.05). In contrast, for IgM antibodies, the frequency of individuals and the number of peptides recognized were higher in the T1, T2 and in the period with no rejection (p<0.05). In summary, IgM autoantibodies directed to CM and Hsp60 were predominant in the physiologic state, in contrast with the predominance of IgG autoantibodies in the pre-Tx period and during rejection. We suggest that the inflammatory environment found in both cardiac diseases and rejection favors the increase of Hsp60 expression and the exposure of cardiac myosin antigens due to cardiomyocyte necrosis. The immune response triggered in this context induces cell activation and isotype switch, from IgM, predominant in the physiologic state, to IgG, more detected in the inflammatory process. In conclusion, we identified a distinct profile of humoral autoimmunity to cardiac myosin and to Hsp60 in the physiologic state and in cardiac transplantation. Further studies will allow us to evaluate the functional activity of these antibodies in the graft and in cells of the immune system; they may have a role in rejection or in the maintenance of homeostasis, in the physiologic context.

A hipertensão arterial sistêmica (HAS) pós-transplante é frequente e está associada com aumento da morbimortalidade cardiovascular e subsequente disfunção do enxerto, sendo relatada como consequência ao uso de imunossupressores, especialmente os inibidores da calcineurina. Este estudo pretende avaliar o impacto da hipertensão arterial sobre a rigidez arterial calculada utilizando o índice ambulatorial de rigidez arterial (IARA) como desfecho substituto obtido pela monitorização ambulatorial da pressão arterial (MAPA) em pacientes transplantados de coração. Trata-se de um estudo prospectivo, observacional, analítico, com grupo controle, realizado no Hospital de Messejana Dr. Carlos Alberto Studart Gomes, hospital público do estado do Ceará, especializado em doenças cardiopulmonares e de referência em transplante de coração. Foram selecionados pacientes adultos transplantados do coração, os quais passaram por exames clínicos e complementares, e um grupo controle com pacientes não transplantados hipertensos. Todos foram submetidos a MAPA e obtenção do IARA com o objetivo de estimar o risco de rigidez arterial. Foram realizados testes estatísticos de significância e regressão logística para controle de confundimento. A média de idade dos transplantados foi de 55 anos, contra 48 dos não transplantados. A hipertensão prévia foi mais frequente em não transplantados, mas diabetes e doença arterial coronariana foram mais frequentes em transplantados. A média diastólica dos transplantados (82) é significativamente maior que a dos não transplantados (74) e o descenso sistólico é praticamente inexistente em pacientes transplantados (-0,18) que no grupo-controle (9,45). A condição de transplantado do paciente não é determinante de rigidez arterial, mas a hipertensão arterial sistólica na primeira avaliação, a média sistólica em 24h, a média diastólica em 24h, o descenso sistólico, o descenso diastólico e o IARA (parâmetros da MAPA) o são. Este estudo encontrou que num grupo de transplantados de coração adultos, a hipertensão arterial sistêmica está independentemente associada com a rigidez arterial estimada pelo IARA, que é um novo método, não invasivo, de fácil execução e de baixo custo. A evidência demonstrada por este estudo pode auxiliar no direcionamento de tratamento dos pacientes transplantados, contribuindo com melhoria do prognóstico / Hypertension post cardiac transplant is frequent and is associated with increased cardiovascular morbidity and mortality and graft dysfunction, being reported because of the use of immunosuppressant, especially the calcineurin inhibitors. This study aims to evaluate the impact of hypertension on the arterial stiffness calculated using the IARA as surrogate outcome obtained by the Home Blood Pressure Monitoring in heart transplanted patients. This is an observational study, analytical, with the control group, in Heart and Lung Messejana´s Hospital, a public institution in the State of Ceará, which is specialized in cardiopulmonary diseases and especially in heart transplant, with adult patients cardiac transplanted, which underwent clinical and complementary exams, from which were obtained the IARA. Statistical significance tests and logistic regression to control for confounding were performed. The average age of transplanted was 55 years, against 48 of the non-transplanted. Hypertension was more frequent in prior not transplanted, but diabetes and coronary artery disease were more frequent in transplanted. The average diastolic of transplanted (82) is significantly higher than the non-transplanted (74) and decrease systolic is virtually nonexistent in transplant patients (-0.18) than in the control group (9.45). The condition of the transplanted patient is not determinant of arterial stiffness (p = 0.105), but are the systolic hypertension in the first evaluation, the average systolic, diastolic average in 12:0 am 12:0 am, systolic, diastolic descent and the IARA (parameters of the HBPM). This study showed that in a group of adult cardiac transplanted, hypertension is independently associated with arterial stiffness estimated by IARA, which is a new method, non-invasive, easy to perform and inexpensive. The evidence demonstrated by this study may assist in treatment of transplanted patients, contributing to improving the prognosis

Após o primeiro ano de transplante cardíaco (TC) o desenvolvimento da doença coronária do transplante se torna a principal causa de morbidade e mortalidade desses pacientes. Neste período, aproximadamente 40% dos pacientes com (TC) desenvolvem hiperlipidemias que contribuem para a gênese da doença coronária do transplante. Alterações no metabolismo lipídico, entre elas, no metabolismo dos quilomícrons e da lipoproteína de baixa densidade (LDL) já foram reportadas no pós transplante. Por outro lado, a concentração da lipoproteína de alta densidade (HDL) nesses pacientes é ainda controversa. Tem sido reportado que a avaliação somente da concentração da HDL não é o suficiente para avaliar todo o papel protetor, portanto aspectos funcionais da HDL devem ser testados. Neste estudo, a propriedade fundamental da HDL de receber lipídeos das outras lipoproteínas foi avaliada em pacientes com TC, através da lipoproteína artificial (LDE). Foi também avaliado o diâmetro da HDL e a sua enzima antioxidante, a paraxonase 1 (PON1). Foram estudados 20 pacientes com TC e 20 indivíduos normolipidêmicos pareados por sexo, idade e índice de massa corpórea. Amostras de sangue foram coletadas, após jejum de 12hs, para determinação do perfil lipídico, glicose, atividade da PON1, diâmetro da HDL e transferência de lipídeos da LDE para a HDL. A concentração de colesterol total e LDL-colesterol não foram diferentes entre os grupos, enquanto a concentração de HDL_colesterol foi menor no grupo TC (p=0.01). A concentração de triglicérides no TC foi aproximadamente 40% (p=0.001). A concentração de apo A-I e apo B foram similares entre os grupos. A glicose plasmática está aumentada nos pacientes transplantados (p=0.008). O diâmetro da HDL é menor nos pacientes do grupo TC quando comparados ao do grupo controle (p=0.047), enquanto a atividade da PON1 não diferiu entre os grupos. A transferência de colesterol e éster de colesterol da LDE para a HDL foi menor em pacientes com TC quando comparados aos controles (p= 0,045 and 0,003 respectivamente). Por outro lado, não encontramos diferenças entre os grupos na transferência de triglicérides e fosfolípides. Os resultados nos mostram que a transferência de colesterol e éster de colesterol está diminuída no TC. Como o éster de colesterol é o principal constituinte do núcleo da HDL, a menor transferência de colesterol para a HDL pode ter contribuído para o menor diâmetro da HDL observado neste grupo. Estas alterações no metabolismo da HDL podem potencialmente desestabilizar o pool de colesterol plasmático e o transporte reverso de colesterol. Este achado pode contribuir para o acelerado processo aterosclerótico que frequentemente ocorre nestes pacientes. / After the first year from the transplantation procedure transplant coronary heart disease becomes a major complication and the leading cause of late morbity and mortality of those patients. After the first year, roughly 40% of heart transplantation (HT) patients develop hyperlipidemias what is implicated in the genesis of transplant coronary heart disease. Alterations in plasma lipid metabolism such as disturbed chylomicron and low-density lipoprotein (LDL) metabolism were also reported. On the other hand, levels of high-densitylipoprotein (HDL) cholesterol are controversy in those patients. It has been perceived that the estimation of the lipoprotein concentration does not suffice to evaluate the overall HDL protective role and that the functional aspects of the lipoprotein should be tested. In this study, the fundamental property of HDL to receive lipids from other lipoproteins modeled by a artificial lipoprotein (LDE) was tested in HT patients, together with size and the HDL-associated antioxidant paraxonase 1 (PON 1). We studied 20 heart transplantation patients and 20 healthy normolipidemic subjects paired for sex, age and body mass index. Blood samples were collected after 12h fasting, for determination plasma lipids, glucose, paraxonase 1 activity, HDL size and transfer of lipids from LDE to HDL. The total cholesterol and LDL cholesterol concentration did not differ in the two groups, whereas HDL cholesterol was smaller in HT (p=0.01). Triglycerides were roughly 40% greater than those of the controls (p=0.001). Apo A-I e apo B concentration values were similar comparing HT patients with controls. Plasma glucose was greater in HT than in controls (p=0.008). HDL particle diameter was smaller in HT patients then in controls (p=0.047), whereas the activity of PON 1 is not different in both groups. The transfer of cholesterol and cholesteryl ester from LDE to HDL were smaller in HT patients than in controls (p= 0.045 and 0.003, respectively). On the other hand, there was no difference in the transfer of triglycerides and phospholipids between HT patients and controls. The results showed that the acceptance of cholesterol and cholesteryl esters by the HDL fraction is diminished in HT. Since cholesteryl ester constitute most of the HDL core and cholesterol is transformed in cholesteryl ester, decreased acceptance of both cholesterol from other lipoprotein particles may account for the smaller HDL particle diameter found in the HT patient group. These alterations in HDL metabolism can potentially destabilizing the plasma cholesterol pool and the reverse cholesterol transport. This finding can contribute for the accelerated atherosclerotic process that commonly occurs in those patients.

INTRODUÇÃO: A rejeição constitui-se em uma das principais causas de mortalidade após o transplante cardíaco pediátrico. O peptídeo natriurético tipo B (BNP), tem sido estudado como método no diagnóstico de rejeição aguda principalmente em pacientes adultos submetidos ao transplante cardíaco. OBJETIVOS: Avaliar o peptídeo natriurético tipo B no diagnóstico de rejeição aguda em crianças submetidas ao transplante cardíaco ortotópico, avaliar o papel do BNP como método adicional não invasivo na elucidação diagnóstica da doença coronariana após transplante e comparar parâmetros clínicos, ecocardiográficos e hemodinâmicos em relação à biópsia endomiocárdica no diagnóstico de rejeição cardíaca aguda. MÉTODOS: Foram coletadas 50 amostras de BNP de 33 crianças em pós-operatório de transplante cardíaco e analisados dados de idade, sexo, cor, grupo sangüíneo, painel imunológico, tempo de evolução após o transplante, sintomatologia, imunossupressão utilizada, número de rejeições, dados ecocardiográficos e parâmetros hemodinâmicos. Os grupos foram divididos em pacientes com rejeição e pacientes sem rejeição. RESULTADOS: Foram analisadas 50 amostras consecutivas de 33 crianças, durante período de 17 meses. A idade mediana foi de 10,1 anos, com predomínio do sexo feminino (54%) e da cor branca (85%). No momento da dosagem de BNP o tempo médio pós-transplante foi 4,3 anos. A biópsia endomiocárdica diagnosticou nove rejeições em oito pacientes (27%), sendo três com grau 3 A, cinco com grau 2 e um com rejeição humoral. No momento da biópsia, a maioria dos pacientes encontrava-se assintomática. O nível sérico de BNP teve mediana de 77,2 pg/ml, sendo 144,2 pg/ml no grupo com rejeição e 62,5 pg/ml no grupo sem rejeição, com p = 0,02. Análise de curva ROC mostra que níveis sangüíneos de BNP maiores que 38 pg/ml apresentam sensibilidade de 100% e especificidade de 56% na detecção de rejeição cardíaca. Os níveis de BNP foram maiores que 100 pg/ml nos pacientes com doença coronariana, com mediana de 167,5 pg/ml, em relação à 15 mediana de 40,5 pg/ml dos pacientes que não apresentaram doença coronariana. A curva ROC mostra ponto de corte de 90 pg/ml como ideal para diagnóstico de doença coronariana, com p = 0,01. Os parâmetros hemodinâmicos não foram diferentes entre os grupos com rejeição e sem rejeição. A sensibilidade do ecocardiograma para detecção de rejeição foi de 44% e especificidade de 90%, com p= 0,02. CONCLUSÕES: Pacientes podem apresentar-se assintomáticos durante episódio de rejeição aguda. O nível sérico de BNP apresentou diferença estatisticamente significante no grupo com rejeição, podendo ser método adicional no diagnóstico de rejeição cardíaca. A doença coronariana esteve associada com níveis elevados de BNP, independente da presença de rejeição aguda. O ecocardiograma mostrou baixa sensibilidade para o diagnóstico de rejeição cardíaca, mas alta especificidade. A avaliação dos parâmetros hemodinâmicos não apresentou neste estudo correlação com os resultados de biópsia. / INTRODUCTION: The rejection is one of the main causes of mortality after pediatric heart transplant. B natriuretic peptide has been used as a diagnostic method for rejection mainly in adult patients after heart transplantation. OBJECTIVE: To correlate BNP levels collected at the moment of endomyocardial biopsy with rejection, to evaluate BNP as an additional method for coronary artery disease and to compare clinical, echocardiograph assessment and hemodynamic parameters with endomyocardial biopsy findings. METHODS: There were 50 BNP blood samples from 33 children submitted to orthotopic cardiac transplantation. Analyzed parameters included: age, gender, race, blood type, reactive panel, functional class, immunosuppressive regimens, number of rejection episodes, echocardiography findings and hemodynamic parameters. The patients were divided in two groups: with rejection and without rejection. RESULTS: Thirty three children with a median age of 10.3 years (54% female) were studied at median time of 4.2 years after heart transplantation. Endomyocardial biopsy diagnosed nine rejection episodes (27%): three were grade 3A; five were grade 2 and one was humoral rejection. At the moment of biopsy most patients were asymptomatic. Average BNP level was 77.2 pg/ml (144.2 pg/ml in the patients with rejection and 65.8 pg/ml in the group without rejection, p=0.02). BNP level was increased in humoral rejection and in patients with coronary artery disease. ROC curve demonstrates BNP levels over 38 pg/ml to present 100% sensibility and 56% specificity to detect acute rejection. The levels of BNP were higher than 100 pg/ml in most of the patients with coronary artery disease (median of 167.5 pg/ml compared with a 40.5 pg/ml in patients without coronary artery disease). The curve ROC shows a critical cut off value for the diagnosis of coronary artery disease at the level of 90 pg/ml in, with p = 0.01. The hemodynamic parameters did not show significant differences between the patients with rejection and the group without rejection. The echocardiogram presented 44% sensibility and a 17 90% specificity to detect the rejection episode (p = 0.02). CONCLUSIONS: Children could be asymptomatic at allograft rejection episodes. BNP level was significantly elevated in children with the allograft rejection episode and may add a valuable information for the rejection assessment. Also, the higher BNP levels associated with coronary artery disease may contribute for its surveillance. Although the echocardiography presented low sensibility to screen for acute rejection episodes, its high specificity enhances its role to structural and functional alterations. The hemodynamic parameters did not contribute for the diagnosis nor presented correlation with the biopsy findings.

Patienten mit schweren Herzerkrankungen, wie z.B. Herzinsuffizienz (HI), zählen zu Risikopatienten in der zahnärztlichen Praxis und erfordern eine besondere Aufmerksamkeit in der zahnärztlichen Betreuung (Prävention, Behandlung und Nachsorge). Das Endstadium der HI führt häufig zur Notwendigkeit einer Kreislaufunterstützung im Sinne eines Herzunterstützungssystems, insbesondere eines sog. left ventricular assist devices (LVAD), und/oder zu einer Herztransplantation (HTx) [4-6] . Patienten nach HTx sind u.a. aufgrund der lebenslangen Immunsuppression als Risikopatienten einzustufen. Auch bei Patienten mit LVAD-Systemen besteht durch die Verbindung der extrakorporalen Steuereinheit nach endothorakal eine erhöhte Infektionsgefahr. In diesem Kontext wurde jedoch festgestellt, dass betroffene Patienten dieser Klientel einen hohen parodontalen Behandlungsbedarf und eine hohe Prävalenz moderater bis schwerer Parodontitis aufweisen. Zudem zeigt sich ein unzureichendes Mundgesundheitsverhalten. Parodontitis erhöht nachweislich das Risiko einer oralen Bakteriämie und schlussendlich das Risiko infektiöser Komplikationen, wie beispielsweise einer Endokarditis. Eine frühzeitige zahnärztliche Behandlung mit langfristiger präventiver Betreuung der genannten Risikopatienten ist daher zu fordern. Die vorliegende Beobachtungsstudie mit prospektiver Verlaufsbeurteilung verfolgte das Ziel festzustellen, ob eine standardisierte (bedarfsorientierte) Zuweisung zum (Haus-)Zahnarzt zu einer verbesserten Mundgesundheitssituation bei Patienten mit HI bzw. Z. n. HTx und LVAD-Implantation führt. Zudem sollten mögliche Ursachen für eine ausbleibende Verbesserung der Mundgesundheit bzw. unzureichende zahnärztliche Therapie aufgezeigt werden. Hierzu wurden zweihunderteins Patienten der Universitätsklinik für Herzchirurgie des Herzzentrums Leipzig im Rahmen einer Querschnittsstudie mit prospektiver Verlaufskontrolle zunächst (standardisiert) zahnärztlich untersucht und befragt (Baseline). Die klinisch-zahnärztliche Untersuchung umfasste die dentale und parodontale Beurteilung der Patienten. Hierfür wurden zum einen fehlende, kariöse und gefüllte Zähne (DMF-T-Index) erfasst und im Weiteren Sondierungstiefen (ST) und Attachmentverlust (AV) erhoben. Aus ST und AV wurde der Schweregrad einer vorliegenden Parodontitis ermittelt (keine/milde, moderate oder schwere Parodontitis). Zudem wurden der dentale und parodontale Behandlungsbedarf aus den vorliegenden Befunden abgeleitet: dentaler Behandlungsbedarf = Vorliegen mindestens einer behandlungsbedürftigen kariösen Läsion (D-T>0), parodontaler Behandlungsbedarf = Sondierungstiefe von ≥3.5mm in mindestens zwei Sextanten. Aus Vorliegen des dentalen und/oder parodontalen Behandlungsbedarfes wurde der gesamtheitliche zahnärztliche Behandlungsbedarf bestimmt. Weiterhin wurde das Mundgesundheits- und Inanspruchnahmeverhalten zahnärztlicher Leistungen mit einem standardisierten Fragebogen ermittelt. Zudem wurde das Mundhygieneverhalten der Patienten (Häufigkeit der täglichen Mundhygiene, Mundhygienehilfsmittel) erfasst. Anschließend erfolgte die standardisierte, zielgerichtete Zuweisung zum (Haus-)Zahnarzt mit einem Arztbrief, welcher die Information über die erfolgte zahnärztliche Untersuchung beinhaltete sowie den aktuell vorliegenden zahnärztlichen Behandlungsbedarf aufzeigte. Nach zwölf Monaten konnten achtundachtzig (HTx = 31, LVAD = 43, HI= 14) der initial untersuchten Patienten erneut unter standardisierten Bedingungen untersucht werden (Follow-up). Hierbei wurden die gleichen Parameter erfasst wie zum Zeitpunkt der Baseline- Untersuchung. Zusätzlich wurden sie in Bezug auf die Zahnarztkonsultation mittels eines standardisierten Fragebogens befragt. Dabei richtete sich die Befragung inhaltlich nach fünf thematischen Schwerpunkten aus: Auswirkung des zahnärztlichen Empfehlungsschreibens auf ein Vorstellen des Patienten beim (Haus-)Zahnarzt, Inhalt des Zahnarztbesuches (z.B. Erfragung der stattgefundenen Therapiemaßnahmen), Antibiotika-Prophylaxe beim (Haus-)Zahnarzt, Fachlicher Kenntnisstand des (Haus-)Zahnarztes in Bezug auf den Umgang mit der Grunderkrankung des Patienten (z.B. regelmäßiges Aktualisieren der Medikamentenanamnese des Patienten), Individuelles Mundgesundheitsverhalten im Zusammenhang mit der Grunderkrankung (z.B. Veränderungen in der persönlichen Mundhygiene seit Diagnosestellung) Die statistische Analyse wurde mit SPSS für Windows, Version 24.0 (SPSS, Inc., US) durchgeführt. Für metrische Parameter wurde der Mann-Whitney-U-Test angewandt. Kategorische Daten wurden mittels Chi-Quadrat- und Fischer-Test analysiert (p<0.05). Zum Zeitpunkt der Eingangsuntersuchung (Baseline) lag der parodontale Behandlungsbedarf der gesamten Patientengruppe bei 91%, die Anzahl der zerstörten Zähne (D-T) bei 0.4 ± 1.5 und die Anzahl fehlender Zähne (M-T) bei 10.7 ± 9.0. Die Auswertung der Fragebögen zeigte, dass die Mehrheit der Patienten (79,5%) der Zuweisung zum (Haus-)Zahnarzt folgte. Dabei waren keine signifikanten Unterschiede in den einzelnen Patientengruppen (HTx: 87%, LVAD: 74%, HI: 79%, p=0.41) festzustellen. Am häufigsten wurde nach Angaben der Patienten, die ihren (Haus-)Zahnarzt besucht hatten, eine professionelle Zahnreinigung (PZR) durchgeführt (53% aller Patienten). In der Gruppe der LVAD-Patienten erhielten jedoch signifikant weniger Patienten eine PZR (40%) als in der Gruppe der HTx- und HI-Patienten (68% und 64%, p=0.04). Lediglich 10% der gesamten Patientengruppe gaben trotz hohem parodontalen Behandlungsbedarf (Baseline 91%) an, dass während der letzten zwölf Monate eine Parodontitistherapie beim (Haus-)Zahnarzt eingeleitet bzw. erfolgt sei. Insbesondere HTx-Patienten gaben an, das Mundgesundheitsverhalten (Häufigkeit der täglichen Mundhygiene, Mundhygienehilfsmittel) seit Beginn der Herzerkrankung konsequenter umzusetzen (HTx: 52% vs. LVAD: 21% und HI: 36%, p=0.03). Ebenso räumten HTx-Patienten der Mundhygiene seit Beginn der Diagnosestellung einen größeren Stellenwert ein (61%), im Vergleich zu LVAD- und HI-Patienten (LVAD: 26% und HI: 21%, p˂0.01). Der Vergleich zwischen Mundgesundheit zum Zeitpunkt der Ausgangsuntersuchung (Baseline) und Kontrolluntersuchung nach zwölf Monaten (Follow-up) zeigt einige Veränderungen: Dabei war ein Anstieg der Karies (D-T; Baseline: 0.4 ± 1.5, Follow-up: 0.6 ± 1.1, p=0.03) und der fehlenden Zähne (M-T; 10.7 ± 9.0 vs. 11.1 ± 9.2, p<0.01) auffällig. Zudem war nur eine geringfügige Reduktion des parodontalen Behandlungsbedarfes der gesamten Kohorte von 91% (Baseline) zu 75% (Follow-up) festzustellen. In der Gruppe der Patienten mit HTx konnten jedoch keine bedeutenden Unterschiede der Mundgesundheits-parameter zwischen Baseline und Follow-up evaluiert werden. In der Gruppe der Patienten mit LVAD zeigte sich im Vergleich Follow-up und Baseline ein leichter Anstieg der fehlenden Zähne (M T; 13.9 ± 8.8 vs. 14.4 ± 9.0, p˂0.01) sowie ein reduzierter parodontaler Behand-lungsbedarf zum Zeitpunkt der Nachuntersuchung (88% vs. 70%, p=0.01). Die HI-Patienten-klientel fällt lediglich durch eine Zunahme der Anzahl fehlender Zähne auf (M-T; 9.8 ± 9.9 vs. 10.3 ± 9.9; p=0.03). Bei der Analyse der Mundgesundheitsparameter unter Berücksichtigung der Ergebnisse der Befragung konnten keine signifikanten Zusammenhänge gezeigt werden; so zeigte beispielsweise der parodontale Behandlungsbedarf keine Assoziationen zu einer nach Angaben der Patienten erfolgten Parodontaltherapie (p=0.69) bzw. zu einem Zahnarztbesuch im Allgemeinen (p=0.54). Des Weiteren gibt es ebenso keine Assoziationen zwischen dentalem Behandlungsbedarf und restaurativen zahnärztlichen Therapiemaßnahmen (p=0.72) sowie Zahnextraktionen (p=0.71). Die einmalige bedarfsorientierte Zuweisung zum (Haus-)Zahnarzt ist schlussendlich nicht ausreichend, um stabile mundgesunde Verhältnisse, insbesondere in Bezug auf die parodontale Behandlungsbedürftigkeit bei Patienten mit schweren Herzerkrankungen zu gewährleisten. Insgesamt liegt ein Verbesserungsbedarf sowohl im Mundgesundheitsverhalten als auch im Mundgesundheitszustand bei Patienten mit HI, LVAD und HTx vor. Obwohl der Status als Risikopatient eine intensive zahnärztliche Betreuung erfordern würde, scheinen die (Haus-)Zahnärzte unter den aktuellen Voraussetzungen nicht imstande zu sein, den derzeitigen parodontalen Versorgungsbedarf schwer Herzerkrankter abzudecken. Eine multidisziplinäre zahnmedizinische Betreuung mit Aufbau und Etablierung von „Special Care“- Einrichtungen mit spezialisierten Zahnärzten ist daher ein zu empfehlender Ansatz. Diese sollten im interdisziplinären Team mit Kardiologen/ Herzchirurgen und anderen beteiligten Fachdisziplinen eine präventionsorientierte Versorgung unter Berücksichtigung der Besonderheiten schwer herzerkrankter Patienten gewährleisten.:Inhaltsverzeichnis Abkürzungsverzeichnis Abbildungsverzeichnis 1 Einleitung 1.1 Einführung 1.2 Risikopatienten in der zahnärztlichen Praxis 1.2.1 Allgemeine Zusammenhänge 1.2.2 Patienten mit schweren Herzerkrankungen (HI, LVAD und HTx) 1.3 Mundgesundheit bei zahnmedizinischen Risikopatienten mit Schwerpunkt auf HI, LVAD und HTx 1.3.1 Bedeutung der Mundgesundheit bei Patienten mit schweren Herzerkrankungen 1.3.2 Mundgesundheitszustand bei Patienten mit schweren Herzerkrankungen (HI, LVAD und HTx/Tx) . . . 1.4 Zahnmedizinische Behandlungsempfehlungen bei Risikopatienten mit Schwerpunkt auf HI, LVAD und HTx 1.5 Ursachenforschung im Hinblick auf eine Verbesserung der Mundgesundheits-situation der Patienten mit schweren Herzerkrankungen . . . . . 1.6 Zielsetzung . . . . . . . . . . . . . 2 Publikationsmanuskript 3 Zusammenfassung der Arbeit 4 Ausblick 5 Literaturverzeichnis 6 Wissenschaftliche Präsentationen 7 Darstellung des eigenen Beitrags 8 Erklärung über die eigenständige Abfassung der Arbeit 9 Lebenslauf 10 Danksagung

Background: Patients treated with an inhibitor of the mechanistic target of rapamycin (mTORI) in a calcineurin inhibitor (CNI)-free immunosuppressive regimen after heart transplantation (HTx) show a higher risk for transplant rejection. We developed an immunological monitoring tool that may improve the identification of mTORI-treated patients at risk for rejection. Methods: Circulating dendritic cells (DCs) and regulatory T cells (Tregs) were analysed in 19 mTORI- and 20 CNI-treated HTx patients by flow cytometry. Principal component and cluster analysis were used to identify patients at risk for transplant rejection. Results: The percentages of total Tregs (p = 0.02) and CD39+ Tregs (p = 0.05) were higher in mTORI-treated patients than in CNI-treated patients. The principal component analysis revealed that BDCA1+, BDCA2+ and BDCA4+ DCs as well as total Tregs could distinguish between non-rejecting and rejecting mTORI-treated patients. Most mTORI-treated rejectors showed higher levels of BDCA2+ and BDCA4+ plasmacytoid DCs and lower levels of BDCA1+ myeloid DCs and Tregs than mTORI non-rejectors. Conclusion: An mTORI-based immunosuppressive regimen induced a sufficient, tolerance-promoting reaction in Tregs, but an insufficient, adverse effect in DCs. On the basis of patient-specific immunological profiles, we established a flow cytometry-based monitoring tool that may be helpful in identifying patients at risk for rejection.

Background: To assess whether the standardized recommendation of patients with heart failure (HF), left-ventricular assist device (LVAD) and heart transplantation (HTx) to visit their dentist leads to improved oral conditions after 12 months. Methods: Patients from the Department of Cardiothoracic Surgery, Leipzig Heart Centre, Germany were examined at baseline and after 12 months. A dental (decayed-, missing-, and filled-teeth index (DMF-T)) and periodontal examination (periodontal probing depth, clinical attachment loss) was performed. At baseline, patients received a standardized recommendation to visit their dentist. At follow-up, a standardized questionnaire regarding the dental consultation was applied. Results: Eighty-eight participants (HTx: 31, LVAD: 43, HF: 14) were included. The majority of patients (79.5%) followed the recommendation to visit their dentist. Within the total cohort, periodontal treatment need was significantly reduced from 91% (baseline) to 75% (follow-up; p < 0.01). Only 10% of total cohort stated that they received periodontal treatment. The outcome in periodontal and dental treatment need at follow-up appointment revealed no statistically significant associations to the questionnaire regarding dentist consultation (p > 0.05). Conclusions: The simple recommendation to visit the dentist appears not enough to obtain sufficient dental and periodontal conditions in patients with severe heart diseases. Thereby, a lack in periodontal treatment of patients with HF, HTx and LVAD was identified, making interdisciplinary dental special care programs recommendable.

Bakgrund: Hjärtat är en stark symbol för människor. Den medicintekniska utvecklingen har förändrat människors livsvillkor och sjuksköterskans arbete. Den tekniska utvecklingen speglar ett behov personcentrerad vård. Detta har väckt ett intresse för hjärttransplantationspatienters upplevelser. Syfte: Att beskriva patienters upplevelser efter en hjärttransplantation. Metod: En litteraturöversikt genomfördes med åtta artiklar. Datainsamlingen genomfördes på databaserna CINAHL och Pubmed. Resultatet analyserade med Fribergs analysmetod. Resultat: Utifrån resultatet framträdde fyra teman: Medicinsk påverkan,sociala relationer, känslomässiga prövningar och en andra chans. Sammanfattning: Litteraturöversikten gav en inblick i hjärttransplantationspatienternas upplevelser efter transplantationen. Dessa handlade om upplevelser av medicinbiverkningar, förändringar i sociala relationer, utmaningar i känsloliv och deras upplevelser efter att ha fått en andra chans på livet. / Background: The heart is a powerful symbol for humans. The technological advancements in medicine have changed people's living conditions and the work of nurses. The technological development reflects a need for person-centered care. This has generated an interest in the experiences of heart transplantation patients. Aim: To describe patients experiences after a heart transplantation. Method: A literature review was conducted utilizing eight articles. Data collection was performed on the CINAHL and PubMed databases. The results were analyzed using Friberg's analysis method. Results: Based on the results, four themes emerged: Medical impact, social relationships, emotional trials, and a second chance. Summary: The literature review provided insight into the experiences of hearttransplant patients post-transplantation. These experiences included encountering medication side effects, changes in social relationships, emotional challenges, and reflections on their experiences after being given a second chance at life.

Background: Extracorporeal photopheresis (ECP) induces immunological changes that lead to a reduced risk of transplant rejection. The aim of the present study was to determine optimum conditions for ECP treatment by analyzing a variety of toleranceinducing immune cells to optimize the treatment. Methods: Ten ECP treatments were applied to each of 17 heart-transplant patients from month 3 to month 9 post-HTx. Blood samples were taken at baseline, three times during treatment, and four months after the last ECP treatment. The abundance of subsets of tolerance-inducing regulatory T cells (Tregs) and dendritic cells (DCs) in the samples was determined by flow cytometry. A multivariate statistical model describing the immunological status of rejection-free heart transplanted patients was used to visualize the patient-specific immunological improvement induced by ECP. Results: All BDCA+ DC subsets (BDCA1+ DCs: p < 0.01, BDCA2+ DCs: p < 0.01, BDCA3+ DCs: p < 0.01, BDCA4+ DCs: p < 0.01) as well as total Tregs (p < 0.01) and CD39+ Tregs (p < 0.01) increased during ECP treatment, while CD62L+ Tregs decreased (p < 0.01). The cell surface expression level of BDCA1 (p < 0.01) and BDCA4 (p < 0.01) on DCs as well as of CD120b (p < 0.01) on Tregs increased during the study period, while CD62L expression on Tregs decreased significantly (p = 0.04). The cell surface expression level of BDCA2 (p = 0.47) and BDCA3 (p = 0.22) on DCs as well as of CD39 (p = 0.14) and CD147 (p = 0.08) on Tregs remained constant during the study period. A cluster analysis showed that ECP treatment led to a sustained immunological improvement. Conclusions: We developed an immune monitoring assay for ECP treatment after heart transplantation by analyzing changes in tolerance-inducing immune cells. This assay allowed differentiation of patients who did and did not show immunological improvement. Based on these results, we propose classification criteria that may allow optimization of the duration of ECP treatment.