A enzima aldeído desidrogenase 2 (ALDH2), localizada na matriz mitocondrial, é crucial na manutenção do balanço intracelular de aldeídos. Atualmente, estima-se que 8% da população mundial apresentam uma mutação pontual no gene da ALDH2 (E487K, ALDH2*2) que confere perda de até 95% na atividade enzimática. No presente projeto utilizamos camundongos knock-in ALDH2*2 para avaliar o impacto da mutação ALDH2 (E487K) na disfunção cardíaca induzida pelo infarto do miocárdio. Observamos que os animais mutantes possuem a atividade da ALDH2 reduzida e desenvolvem disfunção cardíaca e remodelamento ventricular semelhante aos animais selvagens após infarto do miocárdio. Porém, os animais com a mutação E487K possuem uma significante redução no consumo de oxigênio basal (respirometria), máximo (teste físico até a exaustão) e em mitocôndria cardíaca isolada, quando comparados aos animais selvagens. Por fim, o tratamento sustentado com Alda-1 (ativador da ALDH2) foi efetivo em restaurar a função cardíaca dos animais infartados, independente do genótipo. / Aldehyde dehydrogenase 2 (ALDH2), located in the mitochondrial matrix, is critical for the maintenance of cellular redox balance by removing reactive aldehydes produced during oxidative stress. It is estimated that 8% of the world population have a point mutation in the ALDH2 gene (E487K), which reduces its enzymatic activity by 95%. Here, we study the impact of the E487K variant of ALDH2 on myocardial infarction-induced heart failure, using ALDH2 E487K knock-in mice. We observed that mice carrying the ALDH2 variant have reduced ALDH2 activity and protein levels compared to WT mice. Despite of reduced oxidative metabolism, animals with ALDH2 mutation develop cardiac dysfunction and ventricular remodeling equivalent to WT animals after myocardial infarction. Finally, sustained Alda-1 treatment (ALDH2 activator) during 6 weeks improved cardiac function of infarcted animals, regardless of genotype.

Recentemente foi descrito que a deleção dos receptores a2A e a2C adrenérgicos em camundongos, proporciona hiperatividade simpática com evidências de insuficiência cardíaca (IC) aos sete meses de idade. Com isso, esses animais representam um modelo experimental para o estudo de diferentes terapias da IC. Estudamos o efeito de antagonistas b-adrenérgicos (BB) de diferentes gerações em camundongos deleção para os receptores a2A e a2C adrenérgicos (KO) entre cinco a sete meses de idade que apresentam mortalidade de 50%. Foram utilizados camundongos controle (CO) (n = 22) e KO (n = 94) divididos randomicamente e tratados por dois meses com salina, propranolol (P), metoprolol (M) e carvedilol (C). Foi avaliada a pressão arterial, freqüência cardíaca (FC), além da tolerância ao esforço (TE) e fração de encurtamento (FS) do ventrículo esquerdo. A estrutura cardíaca foi avaliada pelo diâmetro dos cardiomiócitos (DC) e a fração de colágeno cardíaco (CC). Aos sete meses de idade os KO tratados com salina apresentaram intolerância ao esforço e redução de 30% na FS, e aumento do DC (13%) quando comparados com os CO. Todos os BB foram eficientes em reduzir a FC de repouso dos KO que tornaram-se semelhantes as dos CO. Nenhum BB restabeleceu a TE nos animais KO. P, M e C restauraram de forma similar a FS nos KO. Apesar de todos os BB reduzirem DC, apenas M restabeleceu as dimensões dos cardiomiócitos que passaram a ser semelhantes as dos CO. Em contrapartida, apenas M reduziu parcialmente o CC. M e C reduziram a mortalidade dos KO em 31 %, sendo que o tratamento com propranolol reduziu a mortalidade dos KO em apenas 24% e foi o BB menos tolerado. Os dados evidenciam o beneficio de M e C no tratamento da IC, e sugerem maior estudo das propriedades farmacodinâmicas de M sobre o remodelamento cardíaco. / We have recently reported that disruption for both a2A ?and a2C adrenergic receptor subtypes in mice (KO) leads to sympathetic hyperactivity with evidence of heart failure (HF) by the age of 7 months. These mice provide a model system for evaluating the efficiency among different ?- adrenergic antagonists (BB) for HF therapy. In the present study, we evaluate the effect of three different BB in a cohort of a wild type (n=22) control group (WT) and a cohort of congenic KO (n=94) from five to seven mo of age. Mice from both groups were randomly assigned to receive by gavage (seven days/wk) either saline (S), propranolol (P), metoprolol (M), or carvedilol (C). Exercise capacity was measured using a graded treadmill protocol. Blood pressure (BP) and heart rate (HR) were determined by tail cuff and LV function by echocardiography. The cardiomyocyte width (CW) and cardiac collagen content (CC) were evaluated by light microscopy. At seven mo of age, when cardiac dysfunction is severe, KO treated with S displayed exercise intolerance and 30% decrease in fractional shortening (FS) when compared with WT. In addition, CW (13%) was increased. All BB were efficient in reducing baseline HR of KO mice towards WT levels, however P was less tolerated. Again, all BB similarly restored FS, and reduced CW, but only M reduced CW towards WT levels. Only M significantly decreased CC. M and C decreased mortality rate of KO mice (31 %), while P did decrease it in only 24%. Collectively these data provide direct evidence for beneficial effect of M and C in restoring cardiac function. Further investigation is need to better understand the pharmacodynamics of M on cardiac remodeling

Recentemente foi descrito que camundongos com ablação dos receptores \'alfa\' 2A and \'alfa\' 2C adrenérgicos (KO) desenvolvem cardiomiopatia induzida por hiperatividade simpática. No presente trabalho caracterizamos o fenótipo desses camundongos aos três e sete meses de idade avaliando a tolerância ao esforço, a função ventricular e a ultraestrutura cardíaca. Além disso, estudamos o efeito da hiperatividade simpática sobre o sistema renina angiotensina (SRA) cardíaco avaliando a expressão de Ang II cardíaca, a atividade da enzima conversora de angiotensina (ECA), a atividade e expressão da renina e a expressão do angiotensinogênio cardíaco. Aos três meses de idade os camundongos KO apresentaram redução de 16% na fração de encurtamento e aumento do diâmetro dos cardiomiócitos em relação ao grupo controle (CO), caracterizando uma cardiomiopatia em estágio inicial. Concomitantemente, os animais KO apresentaram aumento da Ang II, atividade da ECA e expressão do angiotensinogênio cardíacos; e aumento da atividade da renina plasmática. Aos sete meses de idade, os camundongos KO apresentaram intolerância ao esforço, redução de 34% na fração de encurtamento, dilatação do ventrículo esquerdo, retenção hídrica nos pulmões, aumento do diâmetro dos cardiomiócitos e acúmulo de colágeno cardíaco em relação ao grupo CO, caracterizando uma cardiomiopatia grave com sinais clínicos de IC. Nessa fase, os camundongos KO apresentaram aumento da Ang II e expressão do angiotensinogênio cardíacos; e diminuição da expressão e atividade da renina. Dessa forma, os dados evidenciaram a ativação do SRA cardíaco na progressão da cardiomiopatia induzida por hiperatividade simpática / We have recently reported that disruption of both \'alfa\' 2A and \'alfa\' 2C adrenergic receptor subtypes (KO) in mice leads to sympathetic hyperactivity with evidence of heart failure (HF) by seven months (mo) of age. In the present study, we have performed the phenotypical characterization on KO mice at three and seven month of age. In addition, we evaluated the effect of sympathetic hyperactivity on cardiac renin-angiotensin system (RAS) components. For that, we evaluated cardiac Ang II content, angiotensin converting activity (ACE), plasma renin activity and cardiac angiotensinogen expression. At three mo, KO mice displayed reduced fractional shortening (16%) and increased cardiomyocyte width compared with age-matched wild type (WT). Indeed, KO mice showed significantly increased cardiac Ang II content, cardiac ACE activity, angiotensinogen expression and plasma renin activity. At seven mo, KO mice displayed exercise intolerance, reduced fractional shortening (34%), cardiac dilatation, lung edema, increased cardiomyocyte width and increased cardiac collagen content compared with age-matched WT. In addition, KO mice presented an increased cardiac Ang II content and angiotensinogen expression, concomitantly with a decreased plasma renin activity. Collectively, these results uncover potential feedback regulation of cardiac and circulating components of SNS and RAS, which may contribute to a better understanding of the processes taking place during the progression of cardiomyopathy induced by sympathetic hyperactivit.

Introdução: O tratamento quimioterápico com antraciclina está associado à cardiotoxicidade. Sua prevenção primária com o uso de beta-bloqueadores permanece controversa. O objetivo do presente estudo é avaliar o papel do carvedilol na prevenção da cardiotoxicidade relacionada ao tratamento com antraciclina. Métodos: estudo randomizado, duplo-cego, placebo controlado que incluiu 200 pacientes com câncer de mama, fração de ejeção ventricular esquerda (FEVE) preservada e uso de doxorrubicina (240 mg/m²) para receber carvedilol ou placebo até a conclusão da quimioterapia em proporção 1:1. O desfecho primário foi a redução > 10% da FEVE em seis meses. Os desfechos secundários foram o efeito do carvedilol nos marcadores de injúria miocárdica, troponina I (TnI) e peptídeo natriurético cerebral (BNP), e na disfunção diastólica. Resultados: O desfecho primário ocorreu em 14 (14,5%) pacientes do grupo carvedilol e em 13 (13,5%) do grupo placebo (p=1,0). Não houve diferença nos valores da FEVE durante o tratamento quimioterápico ou nos valores de BNP entre os grupos. Houve diferença significativa entre os grupos na distribuição dos níveis de TnI ao longo do tempo, com menor pico de TnI no grupo carvedilol (p=0,003). Além disso, houve menor incidência de disfunção diastólica no grupo carvedilol (p=0,039). Foi observada tendência para menor aumento do diâmetro diastólico do ventrículo esquerdo do início do tratamento até o final da quimioterapia no grupo carvedilol em relação ao placebo, respectivamente, 44,1+3,64 a 45,2+3,2 vs 44,9+3,6 a 46,4+4,0 mm (p=0,057). Conclusão: A incidência de cardiotoxicidade com o uso de doses contemporâneas de ANT foi menor do que relatado previamente com doses mais elevadas. Neste cenário, a administração de carvedilol resultou em redução significativa da injúria miocárdica avaliada pelos níveis de troponina I e pelo aparecimento da disfunção diastólica. No entanto, essa redução não teve impacto na disfunção sistólica relacionada à cardiotoxicidade (NCT01724450) / Background: Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Its prevention with beta-blockers remains controversial. The aim of this prospective, randomized, double-blind, placebo-controlled study was to evaluate the role of carvedilol in the prevention of early onset ANT cardiotoxicity. Methods: We randomized 200 patients with breast cancer and normal left ventricular ejection fraction (LVEF) referred for doxorubicin (240 mg/m²) to receive carvedilol or placebo until completion of chemotherapy. The primary end-point was a reduction > 10% in LVEF at six months. Secondary outcomes were the effects of carvedilol on troponin I (TnI), BNP and diastolic dysfunction. Results: Primary end-point occurred in 14 (14.5%) patients in the carvedilol and in 13 (13.5%) in the placebo (p=1.0). No difference in changes of LVEF or BNP was noted between groups. There was a significant difference between groups on the TnI levels over time, with lower TnI levels in carvedilol group (p=0.003). Additionally, a lower incidence of diastolic dysfunction was seen in carvedilol group (p=0.039). A trend towards less pronounced increase in LV end-diastolic diameter during follow up was noted in the carvedilol group, respectively 44.1+3.64 to 45.2+3.2 vs 44.9+3.6 to 46.4+4.0 mm (p=0.057). Conclusion: In this largest clinical trial of ?-blockers for prevention of early onset cardiotoxicity under contemporary doses of ANT, we noted a lower incidence of cardiotoxicity than higher doses. In this scenario, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction. However, this reduction had no impact on the incidence of cardiotoxicity-related myocardial systolic dysfunction (NCT01724450)

To this day heart failure with preserved ejection fraction (HFpEF) remains a poorly understood malady. Half of all heart failure (HF) cases are HFpEF, and the prevalence of HF is on the rise. Unlike HF with reduced ejection fraction, HFpEF has no treatment options and is often times difficult to diagnose because victims of HFpEF often have pre-existing conditions. Vascular endothelial growth factor (VEGF) has been implicated in maintaining myocardial health and is thought to play a role in HFpEF. We sought to test the hypothesis that VEGF-A plays a role in HFpEF in a hypertensive murine model of HFpEF. Using Western blot analysis we found that there was an up regulation of VEGF-A in the homogenized left ventricle (LV) of our HFpEF mice. Unexpectedly, there was a down regulation of VEGF-A in the homogenized tissue from the aorta in those mice. To study the circulating levels of VEGF in our HFpEF mice we used an ELISA. We found that our HFpEF mice had similar levels of circulating VEGF as our control. This suggests that VEGF has paracrine/autocrine role in our HFpEF model rather than endocrine, like our human data suggested. To identify the cells responsible for the expression profile we saw in the homogenized tissue data we looked at the response of adult rat ventricular myocytes (ARVM) and vascular smooth muscle cells (VSMC) to aldosterone stimulation at short (1hr) and long (24hr) time points at both physiological (50nm) and pathological (1μm) concentrations. To do this analysis we recruited the help of Western blot, ELISA and RT-PCR techniques to construct a consistent VEGF expression profile. The Western blot ARVM data showed statistically significant (P<0.05) increase in VEGF-A to pathological doses of aldosterone, especially at the longer time point. When we tested the VSMC using Western blot analysis, we found that the trend of our n=1 sample suggested a strong response to the physiological dose of aldosterone in the short term. Using the more sensitive ELISA technique to measure the VEGF content of our VCMS we increasing our sample size to n=4 and found no statistically significant (p=NS) response to aldosterone stimulation from the VSMC. However, looking at the trends in the data it is clear that VSMC increases VEGF in response to long-term physiological doses of aldosterone. This is contrary to what we found using Western blot analysis, so we queried the VEGF mRNA from the VSMC to settle the score. Unfortunately, this too proved fruitless. The RT-PCR data was not significant and the trend was that of the ARVM expression profile. We initially turned to VSMC because we hypothesized that they could contribute to the paracrine/autocrine activity similar to what we saw in the LV from the ARVM. It is unclear if VSMC play a role in HFpEF progression, but their lack of consistent response to aldosterone could potential explain the down regulation of VEGF-A we observed in the aorta of our HFpEF mice. We initially sough to test the hypothesis that VEGF-A plays a role in our HFpEF mouse model, what we found was that ARVM contribute to localized VEGF-A increased production in the LV while in the aorta there is a down regulation of VEGF-A in our HFpEF model, we are unable to make any conclusion about VSMC response to aldosterone because of insufficient sample size. Thus in conclusion, it appears that VEGF-A does play a role in our HFpEF model specifically in a paracrine/autocrine manner in the LV where the ARVM contributes to the increased production of the cytokine.

Continuous-flow left ventricular assist devices provide mechanical circulatory assistance for patients suffering from end-stage heart failure that are awaiting or ineligible for heart transplantation. Although actuarial survival and quality of life with these devices is comparable to allograft transplant, they are associated with severe adverse events, including cerebrovascular accidents. Recent advances in continuous-flow technology aim to mitigate the risk of stroke by including design features that minimize flow stasis, turbulence and endothelial dysfunction, as well as promote near-normal pulse pressures. The proposed study is a multicenter, prospective, randomized clinical trial that aims to compare the stroke-free survival and associated incidence and risk of cerebrovascular accidents between three continuous-flow left ventricular assist devices in patients with refractory, end-stage heart failure planning to undergo bridge-to-transplant or destination therapy. Patients will be randomized to receive one of three devices (HeartMate II, Thoratec Corporation, Pleasanton, CA; HeartWare HVAD, HeartWare International Inc., Framingham, MA; HeartMate III, Thoratec Corporation, Pleasanton, CA). Patients will be monitored for stroke-free survival and incidence of cerebrovascular accident for 24 months post-implantation. Investigators will compare stroke-free survival with Kaplan-Meier survival curves and log-rank testing; in addition, investigators will examine each device’s level of risk for causing a cerebrovascular accident with chi square and odds ratio analysis. The data from this study will be used to guide treatment paradigms, device assignment and future development of technologies that mitigate stroke risk in this high-risk population.

Submitted by Mariana Dornelles Vargas (marianadv) on 2015-05-08T17:59:42Z No. of bitstreams: 1 insuficiencia_cardiaca.pdf: 13511668 bytes, checksum: d0a75c3603c6ddc1e31e6c41dbdae4ee (MD5) / Made available in DSpace on 2015-05-08T17:59:42Z (GMT). No. of bitstreams: 1 insuficiencia_cardiaca.pdf: 13511668 bytes, checksum: d0a75c3603c6ddc1e31e6c41dbdae4ee (MD5) Previous issue date: 2011-08-16 / Nenhuma / Atualmente, a insuficiência cardíaca é um dos maiores problemas de saúde pública no mundo devido ao envelhecimento e as mudanças no estilo de vida da população. Estudos demonstraram que a insuficiência cardíaca pode ser considerada uma complicação comum após IAM e, até agora, são modestos os estudos que visam impedir o desenvolvimento de insuficiência cardíaca em indivíduos de alto risco em comparação aos que objetivam novos tratamentos para pacientes após o desenvolvimento de insuficiência cardíaca. Estudos que objetivem a prevenção primária da insuficiência cardíaca, com a identificação dos fatores de risco associados, são de suma importância, pois atingem um número maior de pessoas e, também, contribuem para o manejo dos pacientes com insuficiência cardíaca manifesta. Este estudo investigou a ocorrência de insuficiência cardíaca (IC) e fatores de risco associados em uma coorte prospectiva de pacientes com diagnóstico de síndrome coronariana aguda, com 30 anos ou mais, de ambos os sexos, internados pelo instituto de medicina vascular do Hospital Mãe de Deus de Porto Alegre, RS. O tamanho amostral foi dado pelo ingresso de pacientes entre maio de 2009 e julho de 2010. Foram determinadas, prevalência de IC prévia; incidência aos trinta dias e seis meses após a internação e prevalência no período. As associações entre os fatores de risco e prevalência de IC no período foram analisadas por meio de regressão de Poisson robusta. Dos 125 pacientes incluídos no estudo, 62 (49,6%; IC95% 40,8 a 58,4) apresentaram diagnóstico prévio de IC. Em trinta dias foram observados dois casos novos (0,02%; IC95% 0,006 a 0,04) e em seis meses três novos casos (0,02%; IC95% 0,003 a 0,05). A prevalência de IC no período foi de 53,6% (IC95% 44,8% a 62,3). Na análise ajustada, mantiveram-se associadas ao desfecho as variáveis: baixa escolaridade (p=0,01), IAM prévio (p=0,02) e angioplastia (p=0,02). / Currently, heart failure is a major public health problems in the world due to aging and changes in lifestyle of the population. Studies have shown that heart failure can be considered a common complication after AMI and thus far are modest studies that aim to prevent the development of heart failure in high-risk individuals compared to that aim new treatments for patients after the development of severe heart. Studies that aim at primary prevention of heart failure, with the identification of risk factors are of paramount importance, since it is a larger number of people and also contribute to the management of patients with overt cardiac failure. This study investigated the occurrence of heart failure (HF) and associated risk factors in a prospective cohort of patients with acute coronary syndrome, with 30 years or more, of both sexes admitted by the Institute of vascular medicine at the Hospital Mãe de Deus of Porto Alegre, RS. The sample size was given by the inflow of patients between May 2009 and July 2010. We determined the prevalence of previous HF; effect thirty days and six months after admission and prevalence in the period. The associations between risk factors and prevalence of IC in the period were analyzed using robust Poisson regression. Of the 125 patients enrolled, 62 (49.6%, 95% CI 40.8 to 58.4) had a previous diagnosis of HF. In thirty days we observed two new cases (0.02%, 95% CI 0.006 to 0.04) and in six months three new cases (0.02%, 95% CI 0.003 to 0.05). The prevalence of IC in the period was 53.6% (95% CI 44.8% to 62.3). In the adjusted analysis, remained associated with the outcome variables: low education (p = 0.01), previous AMI (p = 0.02) and angioplasty (p = 0.02).

Cardiomiopatia dilatada (CMD) é uma doença miocárdica caracterizada por dilatação cardíaca e redução da contratilidade da parede do ventrículo esquerdo ou de ambos os ventrículos, sendo a etiologia de origem genética ou desconhecida. Em suínos existem raros relatos de CMD, sendo frequentemente relacionados com intoxicações por ionóforos ou gossipol. Surtos de CMD de etiologia desconhecida em suínos de rebanhos comerciais no Brasil sugeriram a existência de nova etiologia, possivelmente nutricional. Este estudo teve como objetivo investigar as possíveis causas dos surtos de CMD em suínos, a partir de análises macroscópicas, microscópicas, bioquímicas, cromatográficas, moleculares, imuno-histoquímica (IHQ) e reprodução experimental. E teve como resultado 2 artigos científicos. O primeiro artigo descreve os achados clínicos, patológicos, químicos e toxicológicos de três surtos de CMD em suínos de crescimento, além da reprodução experimental desta condição utilizando a ração de uma das propriedades afetadas. Para o estudo experimental utilizou-se 9 animais divididos em 3 grupo; Grupo 1 recebendo ração suspeita, Grupo 2 metade ração suspeita mais metade de ração controle e o grupo 3 recebeu ração controle. Dois suínos do grupo 1 apresentaram condições clínicas e patológicas semelhantes aos casos naturais após 8 dias de consumo da ração suspeita. Os principais sinais clínicos observados eram tosse e dispneia grave. Na necropsia foram constatados dilatação cardíaca bilateral acentuada, hidrotórax, hidropericárdio, edema pulmonar, ascite e fígado com aspecto de noz moscada. O segundo artigo teve como objetivo fazer a caracterização histológica, histoquímica e imuno-histoquímica das lesões cardíacas em 8 suínos com CMD e compara-las com dois suínos controles. As principais lesões evidenciadas foram atrofia de cardiomiócitos, vacuolização sarcoplasmática, ruptura de miofibras e fibras com padrão ondulado evidenciadas nas colorações de hematoxilina e eosina (HE), Tricrômico de Masson e Picrosírius. Na análise imuno-histoquímica utilizando o anticorpo anti-desmina houve uma imunomarcação reduzida ou inexistente em áreas com lesões histopatológicas. A imuno-histoquímica anti-desmina demonstrou ser uma importante ferramenta diagnóstica para caracterização de lesões de CMD em suínos. / Dilated cardiomyopathy (DCM) is a myocardial disease characterized by cardiac dilatation and reduced contractility of the left ventricular wall or both ventricles, the etiology of which is genetic or unknown. In pigs there are rare reports of DCM and are often related to ionosphere or gossypol poisoning. DCM outbreaks of unknown etiology in swine from herds in Brazil suggested the existence of a new, possibly nutritional, etiology. This study aimed to investigate the possible causes of DCM in pigs through macroscopic, microscopic, biochemical, chromatographical, molecular and immunohistochemical (IHC) evaluations, as well as the experimental reproduction of the disease. The project resulted in 2 scientific papers. The first article describes the clinical, pathological, chemical and toxicological findings of three DCM outbreaks in grower pigs, in addition to the experimental reproduction of this condition using the ration of one of the affected farms. For the experimental trial, 9 animals were divided into 3 groups; Group 1 received suspected ration only, Group 2 was fed a diet composed of half suspected ration plus half control ration, and group 3 received control ration only. Two pigs from group 1 presented clinical and pathological conditions similar to the natural cases after 8 days of consumption of the suspected ration. The main clinical signs observed were cough and severe dyspnea. At necropsy, bilateral cardiac dilatation, hydrothorax, hydropericardium, pulmonary edema, ascites and liver with the appearance of nutmeg were observed. The second article aimed to perform the histological, histochemical and immunohistochemical characterization of the cardiac lesions in 8 pigs with DCM and compare it with two control pigs. The main lesions evidenced were cardiomyocyte atrophy, sarcoplasmic vacuolization, rupture of myofibers and fibers with corrugated pattern evidenced in the staining of hematoxylin and eosin (HE), Masson's trichrome (MT) and Picrosírius (PS). Immunohistochemistry analysis using the anti-desmin antibody showed reduced or non-existent immunostaining in areas with histopathological lesions. The anti-desmin IHC proved to be an important tool for the diagnosis and characterization of DCM lesions in pigs.

L'AMP cyclique (AMPc) et le GMP cyclique (GMPc) sont des seconds messagers essentiels pour la régulation de la fonction cardiaque. Leurs niveaux sont régulés par l’adénylate cyclase et la guanylate cyclase, respectivement, et par les phosphodiestérases (PDEs). Cependant, une telle régulation est altérée dans l'insuffisance cardiaque (IC). En effet, la diminution de la signalisation de l’AMPc et l’augmentation de celle du GMPc est caractéristique des cœurs défaillants.Parmi la superfamille des PDEs, la PDE2 a la particularité d'être stimulée par le GMPc, conduisant ainsi à une augmentation remarquable de l'hydrolyse de l'AMPc. Ceci semble induire une interaction entre les voies de signalisation de l’AMPc et du GMPc. Cependant, le rôle de la PDE2 dans le cœur défaillant est très peu connu.Dans ce contexte, nous avons examiné si la PDE2 cardiaque est modifiée dans l’IC chez l’Homme et chez les modèles animaux d’IC, et déterminé le rôle de la PDE2 dans la signalisation β-adrénergique dans les cardiomyocytes. Grâce à l’utilisation de Western blot, de technique radioenzymatique, d’imagerie basée sur le FRET, de la planimétrie, de la microscopie à épifluorescence et des mesures du courant calcique de type L, réalisés sur les tissus myocardiques humains et/ou dans des cardiomyocytes isolés de cœurs des modèles animaux d’IC, respectivement, nous avons montré que l’expression et l’activité de la PDE2 sont augmentées dans les cœurs défaillants. Cette augmentation réduit l’effet d’une stimulation β-adrénergique aiguë, contribuant à la désensibilisation β-adrénergique observée dans l’IC. En accord avec ces résultats, la surexpression de la PDE2 dans des cardiomyocytes sains, réduit l’augmentation des taux d'AMPc et l’amplitude du courant ICa,L et abolit l'effet inotrope positif suite à une stimulation β-adrénergique aiguë, sans affecter la contractilité basale. Plus important, les cardiomyocytes surexprimant la PDE2, montrent une protection contre les réponses hypertrophiques induites par la noradrénaline et contre les arythmies induites par l'isoprotérénol.En conclusion, ce travail met en évidence l'altération de la PDE2 dans l’IC et nous laisse suggérer que l’augmentation de la PDE2 dans l’IC peut constituer un mécanisme de défense important dans des conditions de stress cardiaque, notamment en antagonisant la suractivation de la voie β-adrénergique. Ainsi, l'activation de PDE2 myocardique peut représenter une nouvelle stratégie thérapeutique anti-adrénergique intracellulaire dans l’IC. / Cyclic AMP (cAMP) and cyclic GMP (cGMP) are critical second messengers for the regulation of cardiac function. Their levels are regulated by adenylyl and guanylyl cyclases, respectively, and by cyclic nucleotides phosphodiesterases (PDEs). However, such regulation is altered in heart failure (HF). Indeed diminished cAMP- and augmented cGMP-signaling is characteristic of failing hearts.Among the PDE superfamily, PDE2 has the unique property to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis. This appears to mediate a negative cross-talk between cAMP- and cGMP signaling pathways. However, the role of PDE2 in the failing heart is only poorly understood.In this context, we investigated whether myocardial PDE2 is altered in human and experimental HF and determined PDE2 mediated effects on β-adrenoceptor (β-AR) signaling in cardiomyocytes. Using immunoblotting, radioenzymatic- and FRET-based assays, video-edge-detection, epifluorescent microscopy and L-type Ca2+ current measurements, performed in myocardial tissues and/or isolated cardiomyocytes from human and/or experimental HF, respectively, we showed that PDE2 is markedly upregulated in failing hearts. This reduces the effect of an acute β-adrenergic stimulation, and contributes to the β-adrenergic desensitization which is a characteristic feature in HF. Accordingly, PDE2 overexpression in healthy cardiomyocytes reduced the rise in cAMP levels and ICa,L amplitude and abolished the inotropic effect following acute β-AR stimulation, without affecting basal contractility. Importantly, PDE2-overexpressing cardiomyocytes showed marked protection from norepinephrine-induced hypertrophic responses and from isoproterenol-induced arrhythmias.In conclusion, this work highlights the alteration of PDE2 in HF and lets us assume that PDE2 upregulation in HF may constitute an important defence mechanism during cardiac stress, e.g. by antagonizing excessive β-AR drive. Thus, activating myocardial PDE2 may represent a novel intracellular anti-adrenergic therapeutic strategy in HF.

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