La cardiomyopathie dilatée est l'une des principales causes d'insuffisance cardiaque en Europe. Dans le cadre de la cardiomyopathie liée aux mutations du gène LMNA, en dépit des soins médicaux conventionnels, aucun traitement satisfaisant ne permet de pallier à la dilatation cardiaque progressive et à la perte de la contractilité. Le gène LMNA code pour les lamines nucléaires de type A, qui sont les principaux constituants de la lamina nucléaire. De précédents travaux démontrent que l'activation anormale de ERK 1/2 est impliquée dans la pathophysiologie de la cardiomyopathie dilatée liée aux mutations du gène LMNA. L'inhibition de la voie ERK 1/2 ralentit également la progression de la fibrose myocardique, relativement développée chez l'homme, en cas de cardiomyopathie dilatée. Dans le cadre de ma thèse, j’ai suggéré que l'activité aberrante de la voie TGF-β pourrait participer à l’activation anormale de ERK 1/2 et être impliquée dans la physiopathologie de dysfonction contractile ventriculaire gauche dans la cardiomyopathie liée aux mutations du gène LMNA. Les mécanismes moléculaires sous-jacents à la modulation de la signalisation ERK1/2, causée dans le cœur, par les mutations du gène LMNA, restent totalement incertains. De ce fait, j'ai testé l'hypothèse selon laquelle la modulation anormale de ERK1/2 induirait l'altération des cibles cytosoliques et modifierait le réseau du cytosquelette cardiaque. Mon travail a mis en évidence un nouveau partenaire de la forme active (phosphorylée) d’ERK1/2 : cofiline-1. La cofiline induit la déramification des filaments d'actine. Ce projet met en lumière un rôle inattendu joué par la signalisation ERK1/2 dans la dynamique de l'actine et dans le développement de la dysfonction ventriculaire gauche de la cardiomyopathie liée aux mutations du gène LMNA. / Dilated cardiomyopathy is one of the leading causes of heart failure in Europe. Despite of the conventional medical care, there is no definitive treatment for the progressive cardiac dilatation and loss of contractility in LMNA cardiomyopathy often leading to sudden death or heart transplantation. LMNA gene encodes nuclear A-type lamins, which are the main constituents of the nuclear lamina. Previous studies clearly show that the abnormal ERK1/2 activation is involved in the pathophysiology of LMNA dilated cardiomyopathy. However, its role in the development of cardiac dysfunction remains unclear. Inhibition of ERK1/2 signaling also slows progression of myocardial fibrosis, which is prominent in humans with dilated cardiomyopathy. I suggested that aberrant TGF-β signaling activity could participate to the abnormal ERK1/2 activation and be involved is the pathophysiology of left-ventricular contractile dysfunction in LMNA cardiomyopathy. Given that the understanding of molecular and cellular mechanisms underlying the modulation of ERK1/2 signaling in the heart caused by LMNA mutation remains totally unclear, I tested the hypothesis that ERK1/2 abnormal modulation leads to alteration of cytosolic targets and alter cardiac cytoskeleton network. My work highlighted a novel partner of activated (phosphorylated) ERK1/2, ADF/cofilin-1. Cofilin promotes debranching of actin filaments. I showed that disrupted actin dynamics leads to abnormal sarcomere structure. This project unraveled an unexpected role played by ERK1/2 signaling in actin dynamics and in the development of left-ventricular dysfunction in LMNA cardiomyopathy.

Introduction: Inflammatory cardiomyopathy (DCMi) represents a non-familial form of dilated cardiomyopathy (DCM) and endomyocardial biopsy (EMB) is crucial for its diagnosis. Aims: To assess the prevalence of DCMi in patients with DCM of unclear origin, to evaluate the significance of serological tests for antibodies against infectious cardiotrophic agents and to analyze the effect of specific therapy guided by EMB results. Methods: EMB was performed in 56 subjects (mean age 52 ± 10 years) with DCM of unclear etiology and left ventricular (LV) ejection fraction (EF) < 40% with a history of heart failure less than 1 year. EMB samples were analyzed by immunohistochemistry, polymerase chain reaction (PCR) and electron microscopy. Results: Immunohistochemical examination revealed myocardial inflammation in 26 patients (46%), the PCR method detected genome of microbial agents in 32 patients (57%). Electron microscopy showed the presence of particles of microbial agents in 41 patients (73%). Serological blood tests found no IgM antibody positivity against any of the investigated microbial agents. Targeted antibiotic therapy in patients with evidence of Borrelia burgdorferi (Bb) genome in the EMB led to a reduction in LV size, improvement of LV EF and alleviate symptoms of heart failure. Conclusion: DCMi...

A proteína S100B é considerada um marcador bioquímico para lesão cerebral. Entretanto, foi demonstrado que há liberação de S100B em coração isolado de rato. Neste estudo, investigou-se os níveis séricos de S100B em pacientes portadores de cardiomiopatia dilatada (CMD). Métodos e Resultados: Foram selecionados 21 pacientes com CMD, excluindo qualquer condição que pudesse influenciar os níveis séricos de S100B. O grupo controle foi composto por 21 indivíduos pareados por sexo e idade. Ambos os grupos foram submetidos à avaliação clínica, ecocardiográfica, mensuração da proteína S100B e de NT-proBNP (expressos como mediana [variação interquartil]). Os níveis de NT-proBNP no grupo de pacientes (1462 pg/ml [426 - 3591]) foram maiores do que no grupo controle (35 pg/ml [29 - 55]); P<0.001. Os níveis de S100B foram maiores no grupo de pacientes (0.051µg/L [0.022 - 0.144]) do que no grupo controle (0.017µg/L [0.003 - 0.036]); P=0.009. Houve correlação positiva entre os níveis séricos de S100B e NT-proBNP somente no grupo de pacientes (Coeficiente de Spearman r=0.534; P=0.013). Conclusão: A proteína S100B está aumentada na CMD. Embora não possamos excluir a influência de dano cerebral, houve uma correlação positiva entre os níveis séricos de S100B e NT-proBNP em pacientes com CMD / The S100B protein is considered a biochemical marker for brain injuries. However, the isolated rat heart releases S100B. In this study, the serum levels of S100B was investigated in dilated cardiomyopathy (DCM) patients in order to evaluate its levels in heart disease. Methods and Results: It was selected DCM patients, excluding any condition that could influence S100B serum levels. Control individuals were sex and age matched. Both groups were submitted to clinical evaluation and echocardiography. The S100B and NT-proBNP serum levels (expressed as median [interquartile range]) were measured. NT-proBNP levels in patients group (1462 pg/ml [426 - 3591]) were higher than in controls (35 pg/ml [29 - 55]); P<0.001. S100B serum levels were higher in patients group (0.051µg/L [0.022 - 0.144]) than in controls (35 pg/ml [29 - 55]); P<0.001. S100B serum levels were higher in patients group (0.051µg/L [0.022 - 0.144]) than in controls (0.017µg/L [0.003 - 0.036]); P=0.009. Additionally, a positive correlation between S100B and NT-proBNP serum levels only in patients group (Spearman\'s coefficient r=0.534; P=0.013) was found . Conclusions: Although the influence of S100B from brain cannot rule out, the positive correlation between S100B and NT-proBNP levels in DCM patients points to the myocardium as the main source for the rise in S100B serum levels

A cardiomiopatia dilatada (CMD) é uma doença freqüente na clínica veterinária que acomete, principalmente, a espécie canina, habitualmente os machos, jovens ou adultos-jovem, das raças grandes e gigantes, em especial Doberman e Boxer. A doença caracteriza-se por uma redução na contratilidade e, freqüentemente, por arritmias que resultam na diminuição do volume sistólico e do débito cardíaco. O tratamento convencionalmente preconizado para cães acometidos pela CMD consiste na prescrição de vasodilatadores, agentes inotrópicos positivos (digitálico), diuréticos, dieta hipossódica e, quando necessário, antiarrítmicos. A ativação do sistema nervoso simpático (SNAS) ocorre em resposta à redução do débito cardíaco e da pressão arterial observados em casos de insuficiência cardíaca. Porém a partir de um certo grau os efeitos hipertensivos, cronotrópicos e inotrópicos positivos do SNAS geram graves alterações cardíacas como a sobrecarga de pressão e volume nos ventrículos, conseqüente isquemia miocárdica, morte de miócitos com deposição de tecido conjuntivo, diminuição da contratilidade cardíaca e nova sobrecarga de pressão e volume. O carvedilol é um &beta;-bloqueador de 3a geração, não seletivo, que bloqueia igualmente e competitivamente os receptores &beta;1, &beta;2 e &beta;1. O carvedilol produz uma evidente vasodilatação periférica, exerce efeitos anti-oxidantes, removendo radicais livres de oxigênio e prevenindo a peroxidação lipídica nas membranas cardíacas, prevenindo a perda de miócitos e a ocorrência de arritmias e reduzindo a taxa de mortalidade em pacientes humanos. O objetivo do presente estudo foi avaliar clínica, eletrocardiográfica, radiográfica e ecocardiograficamente a evolução de cães com cardiomiopatia dilatada (CMD) tratatos com terapia convencional associada ao carvedilol. Para tal foram avaliados 49 cães com CMD divididos em: grupo NT, tratado com terapia convencional, e grupo T, tratado com terapia convencional associada ao carvedilol. Os animais foram submetidos à avaliação clínica e a exames complementares durante o período de um ano. Os resultados demonstraram que a terapia com carvedilol apresentou boa tolerabilidade na dose de 0,3 mg/kg/12-12horas, aumentou a sobrevida dos cães em 30,9%, não alterou as pressões sistólica e diastólica, reduziu a freqüência cardíaca após três semanas de terapia, melhorou significantemente as frações de encurtamento e ejeção após seis meses de tratamento, não promoveu alterações radiográficas e da distância E-septo, diminuiu o índice de letalidade da doença, fato demonstrado pela melhora no escore clínico e na classe funcional dos animais, obtidas após três semanas de terapia com carvedilol. / Dilated cardiomyopathy (DCM) is a frequent disease in veterinary clinics which occurs specially in dogs, mostly males, young or young-adults, of big and giant breeds, mainly Dobermans and Boxers. The disease is characterized by a reduction in contractility and, frequently, by arrhythmias resulting in decrease of systolic volume and cardiac output. Commonly prescribed therapy for dogs presenting DCM consists of vasodilators, positive inotropic drugs (digitalics), diuretics, low-sodium diet and, when necessary, anti-arrhythmics. Activation of sympathetic nervous system (SNS) occurs in response to decrease in cardiac output and arterial pressure observed in cases of heart failure. However, after a certain degree, hypotensive, chronotropic and positive inotropic effects of SNS lead to severe heart alterations like pressure and volume overload on ventricles with consequent myocardial ischemia, death of myocytes with connective tissue deposition, decrease in heart contractility, and again pressure and volume overload. Carvedilol is a third generation non-selective ?- blocker which blocks equally and competitively &beta;1, &beta;2 and &beta;1 receptors. Carvedilol produces an evident peripheral vasodilation, exerts anti-oxidative effects, removing free radicals of oxygen and preventing lipidic peroxydation of cardiac membranes, and the loss of myocytes and arrhythmias, as well as reducing mortality rate in human patients. The aim of the present study was to evaluate by physical examination, electrocardiography, radiography, and echocardiography the evolution of dogs with dilated cardiomyopathy (DCM) treated by conventional therapy associated to carvedilol. Forty-nine dogs with DCM were divided in two groups: group NT: treated with conventional therapy, and group T: treated with conventional therapy associated to carvedilol. The animals were submitted to clinical and complementary examinations during one year. The results demonstrated that carvedilol therapy presented good tolerability on the dose of 0,3 mg/Kg each 12 hours, prolonged lifetime of the dogs in 30,9%, did not alter systolic or diastolic pressure, reduced heart frequency after three weeks of treatment, significantly enhanced shortening and ejection fractions after six months of treatment, did not promote radiographic or E-septum distance alterations, decreased patients letality, as demonstrated by improvement of clinical score and functional class (heart failure according to NYHA) of the animals, obtained three weeks after the beginning of cavedilol therapy.

Orientador: Orlando Petrucci Junior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T10:51:42Z (GMT). No. of bitstreams: 1 Souza_FernandoSergioOlivade_D.pdf: 1025341 bytes, checksum: 15ba5e4c6177129ac03b697eb1f59cb9 (MD5) Previous issue date: 2008 / Resumo: A estimulação elétrica biventricular apresenta bons resultados no tratamento da insuficiência cardíaca congestiva refratária em portadores de cardiomiopatia dilatada com distúrbios de condução interventricular. OBJETIVO: Apresentar proposição utilizando técnica original simplificada para o implante de eletrodo de estimulação ventricular esquerda epicárdica, baseado na anatomia radiológica e no eletrograma intracavitário,enfatizando o componente atrial, demonstrando o resultado, complicações, ressaltando tempo total de utilização de fluoroscópio. CASUÍSTICA E MÉTODO: De Outubro de 2001 a Março de 2007 foram realizados 234 implantes de marca-passo biventricular em pacientes previamente selecionados, utilizando-se anatomia radiológica e observação de eletrograma intracavitário, dando-se prioridade ao componente atrial, demonstrando a taxa de sucesso, complicações e tempo total de utilização de radioscopia. RESULTADOS: O implante do sistema, utilizando-se a estimulação do ventrículo esquerdo via seio coronariano não foi possível em 19(8,1%) pacientes. Em 30(12,8%) pacientes foram observadas dificuldades na canulação do óstio coronário e em 52(22%) pacientes observaram-se dificuldades de progressão do eletrodo através do seio coronário. O tempo médio de utilização de radioscopia foi 18,69(±15,2) min. CONCLUSÃO: A utilização da técnica simplificada para cateterização do seio coronário sem utilização de bainha, baseada na anatomia radiológica e no eletrograma intracavitário, enfatizando o componente atrial, no tratamento de portadores de cardiomiopatia dilatada avançada, pela terapia de ressincronização cardíaca, demonstrou resultado satisfatório, índice de complicações pequeno, e baixa exposição do operador a radiação ionizante / Abstract: Biventricular pacing has present good results in treatment of congestive cardiac heart failure in patients with dilated miocardyopathy and interventricular conduction disturbance. PURPOSE: to present a proposal of using a original simplified technique for left epicardial ventricular lead stimulation, based on the radiological imaging of the anatomy and intracavitary electrogram, emphasizing the atrial component, showing the results, complications, highlighting the total fluoro time. METHODS: From October, 2001 up to March, 2007, 234 biventricular pacemaker implantations were performed in previously selected patients, using radiological anatomy and observation of the intracavitary electrogram, focusing on the atrial component, and showing the success rate, complications and total time of radioscopy utilization. RESULTS: The implantation of the system using left ventricular pacing via coronary sinus was not possible in 19(8,1%) patients. Difficulties on the cannulation of the coronary ostium were felt in 30(12,8%) patients and difficulties of lead advancement through the coronary sinus were felt in 52(22%) patients. The mean time of radioscopy utilization was 18.69(±15,2) min. CONCLUSION: the use of a simplified technique for coronary sinus cannulation without the aid of a sheath, based on the radiological imaging of the anatomy and intracavitary electrogram, emphasizing the atrial component, for the treatment of advanced dilated cardiomyopathy patients with cardiac resynchronization therapy, has shown satisfactory results, low incidence of complications, and low exposure of the operator to ionizing radiation / Doutorado / Cirurgia / Doutor em Cirurgia

Cardiomiopatia dilatada (CMD) é uma das doenças cardiovasculares adquiridas mais comuns em cães afetando principalmente cães de raças grandes e gigantes, além do Cocker Spaniel Inglês e Americano. A anormalidade primária é a diminuição da contratilidade miocárdica, com dilatação secundária das câmaras cardíacas, que pode evoluir para insuficiência cardíaca, apresentar arritmias (atrial e/ou ventricular) e resultar em óbito em qualquer estágio da doença (sendo a morte súbita relativamente comum). Poucos estudos em cães, sendo a maioria retrospectiva, têm o objetivo de determinar fatores prognósticos, e predizer o prognóstico em qualquer paciente continua a ser um desafio. Portanto, no presente trabalho objetivou-se estudar a sobrevida de cães com CMD, assim como observar possíveis fatores determinantes de sobrevida. Para tal, foram avaliados 50 cães com CMD por meio de exame físico, radiográfico de tórax, eletrocardiográfico (eletrocardiograma de repouso e monitorização Holter) e ecocardiográfico. Os animais foram acompanhados por pelo menos 150 dias ou até o óbito. Avaliou-se a influência da idade, raça, sexo, fração de encurtamento do ventrículo esquerdo (FE), da classe funcional da insuficiência cardíaca, da presença de ascite, efusão pleural, edema pulmonar, insuficiência cardíaca bilateral, fibrilação atrial (FA) ou de arritmias ventriculares na sobrevida. A sobrevida dos cães com CMD variou de cinco dias a 1021 dias, com tempo médio de 347 dias, e tempo mediano de sobrevida foi de 223 dias; a probabilidade de sobreviver por seis meses foi de 51%, por um ano foi de 37% e por dois anos foi de 13%. Os cães da raça Cocker Spaniel Inglês apresentaram maior sobrevida em relação aos cães da raça Doberman e aos cães de outras raças. A presença de FA (p<0,03) e de arritmias ventriculares (tanto de ectopias ventriculares no eletrocardiograma de repouso (p<0,02) como de taquicardia ventricular não sustentada (p<0,0001) na monitorização Holter) foram associadas a menor sobrevida, enquanto que a idade, FE, sexo, classe funcional da insuficiência cardíaca, presença de ascite, efusão pleural, edema pulmonar ou insuficiência cardíaca bilateral não estiveram associados a aumento da mortalidade. A sobrevida foi variável, mas o prognóstico em geral foi ruim. O melhor preditor diagnóstico foi a presença de taquicardia ventricular não sustentada na monitorização Holter. / Dilated cardiomyopathy (DCM) is one of the most common acquired cardiovascular disease of dogs, affecting mainly large and giant breeds, as well as English and American Cocker Spaniels. The primary abnormality is decrease in myocardial contractility with secondary cardiac chambers dilatation. The clinical presentation may include development of heart failure, arrhythmias (atrial and/or ventricular), and death in any phase of the disease (with sudden death relatively frequent). Few studies have been described in dogs with the purpose of determining prognostic indicators for DCM, and predicting prognosis in any given single patient continues to be a challenge. The aim of this study was to evaluate survival time, and if possible, to find factors influencing prognosis in dogs with dilated cardiomyopathy. Fifty dogs with DCM have been included in the study. The patients were prospectively evaluated by physical examination, ten-lead electrocardiography, thoracic radiography, 24-hour Holter monitoring, and echocardiography. The animals were followed-up for at least 150 days or until death. Studied variables were left ventricle shortening fraction, age, sex, breed, presence of ascite, subcutaneous edema, pulmonary edema, pleural effusion, biventricular heart failure, as well as, presence of atrial fibrillation and ventricular arrhythmias, including non-sustained ventricular tachycardia on Holter monitoring. The mean and median survival time were, respectively, 347 days and 223 days (range 5 to 1021 days). Probability of survival at six months was 51%, at 1 year was 37%, and at 2 year was 13%. The survival time was significantly longer in English Cocker Spaniel, versus Doberman Pinschers, or versus other breeds. Atrial fibrillation (p<0,03) and ventricular arrhthmias (ventricular ectopy on ten-lead electrocardiography (p<0,02) and non-sustained ventricular tachycardia (p<0,0001) on Holter monitoring) were associated with increased mortality. While age at the time of presentation, shortening fraction, gender, presence of ascites, pleural effusion, or pulmonary edema were not associated with increased mortality. Survival time was variable, but the prognosis was usually poor. The best prognostic indicator was the presence of non-sustained ventricular tachycardia in Holter monitoring.

Les Entérovirus humains du groupe B (EV-B) et plus spécifiquement les virus Coxsackie B sont considérés comme une cause majeure des myocardites infectieuses aigues et chroniques dont 10% peuvent évoluer vers la cardiomyopathie dilatée (CMD). Les mécanismes moléculaires viraux impliqués dans la progression de la myocardite aiguë vers le stade de la CMD ne sont pas élucidés.L’analyse par séquençage NGS a montré chez 8 (33%) des 24 patients atteints de CMD inexpliquée l’existence de populations majoritaires tronquées de 19 à 50 nucléotides associées à des formes virales minoritaires complètes. La proportion de populations tronquées s’est révélée négativement corrélée au ratio ARN+/ARN- et à la charge virale. Des études immuno-histologiques et par hybridation in situ des tissus cardiaques ont montré que le clivage de la dystrophine était uniquement retrouvé dans les cardiomyocytes infectés par les EV-B. Pour étudier les activités de réplication des populations d’EV-B persistants, un réplicon (CVB3-emGFP) a été généré à partir d’une souche cardiotrope (CV-B3/28). La transfection d’ARN de synthèse complets et tronqués (d50) dans des cultures de cardiomyocytes humains primaires a mis en évidence des mécanismes de recombinaison et/ou de trans-complémentation entre ces 2 formes virales induisant de faibles activités de réplication.Nos résultats démontrent l’existence de mécanismes de coopération moléculaire entre des populations d’EV-B tronquées et complètes qui pourraient expliquer la mise en place du mécanisme de persistance virale observée au cours de la phase clinique de CMD. Ces résultats pourraient contribuer au développement de nouvelles stratégies thérapeutiques pour prévenir et traiter les infections cardiaques à EV-B. / Enteroviruses group B (EV-B) and more specifically Coxsackievirus B are recognized as major causes of acute and chronic infectious myocarditis, which 10% may progress towards dilated cardiomyopathy (DCM). Viral molecular mechanisms involved in the progression from acute myocarditis to the clinical stage of DCM remain unknown.Deep sequencing analysis showed in 8 (33%) of 24 unexplained DCM patients the existence of major CVB3 populations with deletions of 19 to 50 nucleotides associated with a minority of complete viral forms. The proportion of deleted viral populations was negatively correlated with RNA+/RNA- ratio and the viral load levels. Immuno-histological and in situ hybridization assays of DCM cardiac tissues demonstrated that the cleavage of dystrophin was found only in cardiomyocytes infected with EV-B. To study the replication activities of persistent EV-B populations, a replicon (CVB3-emGFP) was generated from a cardiotropic strain (CV-B3/28). Transfection of synthesized complete and truncated (d50) viral RNAs in primary human cardiomyocytes cultures revealed mechanisms of recombination and / or trans-complementation between these two viral forms inducing low replication activities.In conclusions, our original results demonstrated the existence of new molecular mechanisms of cooperation between EV-B deleted and complete viral populations that could explain the development of a viral persistence mechanism observed during the clinical phase of DCM. These findings may contribute to the development of new therapeutic strategies to prevent and treat persistent heart EV-B infections.

La cardiomyopathie dilatée (CMD) est caractérisée par une fraction d’éjection (FE) réduite, une fonction systolique altérée, une désorganisation de la matrice extracellulaire et des défauts métaboliques. Dans différents modèles de CMD, le niveau d’expression de la nicotinamide riboside kinase 2 (Nmrk2) impliquée dans la synthèse du NAD, un coenzyme majeur du métabolisme énergétique et une molécule de signalisation, est augmenté. NMRK2 est identique à « Muscle Integrin Binding Protein » se liant à l’hétérodimère intégrine β1/α7. Le rôle de Nmrk2 dans le cœur n’est pas connu. Les souris Nmrk2-KO jeunes développent une réponse hypertrophique concentrique normale en réponse à l’angiotensine II et à la constriction aortique. Les échocardiographies jusque 8 semaines post-TAC et au cours du vieillissement à l’état basal, montrent une diminution plus sévère de la FE et un développement de CMD. Les RT-QPCR montrent une augmentation du niveau d’expression de l’isoforme lente β de myosine. NMRK2 n’est pas requise pour maintenir le taux de NAD dans le cœur en réponse aux traitements pro-hypertrophiques et à un âge jeune. Par contre, au cours du vieillissement, les niveaux d’expression de Nmrk1 et Nampt sont diminués et à 24 mois, le NAD myocardique est réduit de 50% chez les souris Nmrk2-KO. A ce même âge, le complexe α7β1 est réduit. Les analyses histologiques montrent un défaut du dépôt de la laminine, la présence d’une fibrose et un élargissement de l’espace intercellulaire chez le mutant Nmrk2-KO. NMRK2 est requise pour préserver la fonction et la structure cardiaque et l’homéostasie du NAD à un âge avancé. Des composants moléculaires modulant sa voie pourraient être une option thérapeutique. / Dilated cardiomyopathy (DCM) is a severe heart disease characterized by reduced ejection fraction, altered systolic function, extracellular matrix disorganization and metabolic defects. In different mice models of DCM, the expression of the nicotinamide riboside kinase 2 (Nmrk2) implicated in the synthesis of NAD, a major coenzyme in energy metabolism and a signaling molecule, is increased. NMRK2 is similar to the muscle integrin binding protein (MIBP) that binds to the integrin α7β1 heterodimer. The role of Nmrk2 in the heart is unknown. Young Nmrk2-KO mice develop a normal cardiac hypertrophic response to angiotensin-II exposure and transverse aorta constriction (TAC) but follow-up echocardiography until 8 weeks post-TAC and during aging from 5 to 24 months revealed a more severe decrease in the EF and the development of a DCM phenotype. RT-qPCR analysis of cardiac mRNAs showed an increase in the slow, cardiac, β myosin heavy chain isoform starting at 12 months. NMRK2 was not essential to maintain myocardial NAD levels in response to pro-hypertrophic treatments and in young adults. However Nmrk1 and Nampt expression level declined strongly with aging and Nmrk2-KO mice displayed a 50% reduction in myocardial NAD levels at 24 months. The α7β1 integrin complex was repressed at this age. Immunofluorescent analyses and electron microscopy revealed a defect in laminin deposition and enlarged intercellular space in the Nmrk2-KO heart. The Nmrk2 gene is required to preserve cardiac function and structure during aging and becomes indispensable for maintaining NAD at late age. Molecular characterization of compounds modulating this pathway could give future therapeutic prospect.

Introduction: Inflammatory cardiomyopathy (DCMi) represents a non-familial form of dilated cardiomyopathy (DCM) and endomyocardial biopsy (EMB) is crucial for its diagnosis. Aims: To assess the prevalence of DCMi in patients with DCM of unclear origin, to evaluate the significance of serological tests for antibodies against infectious cardiotrophic agents and to analyze the effect of specific therapy guided by EMB results. Methods: EMB was performed in 56 subjects (mean age 52 ± 10 years) with DCM of unclear etiology and left ventricular (LV) ejection fraction (EF) < 40% with a history of heart failure less than 1 year. EMB samples were analyzed by immunohistochemistry, polymerase chain reaction (PCR) and electron microscopy. Results: Immunohistochemical examination revealed myocardial inflammation in 26 patients (46%), the PCR method detected genome of microbial agents in 32 patients (57%). Electron microscopy showed the presence of particles of microbial agents in 41 patients (73%). Serological blood tests found no IgM antibody positivity against any of the investigated microbial agents. Targeted antibiotic therapy in patients with evidence of Borrelia burgdorferi (Bb) genome in the EMB led to a reduction in LV size, improvement of LV EF and alleviate symptoms of heart failure. Conclusion: DCMi...

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