Perfil clínico e incidência de eventos cardiovasculares em 36 meses em pacientes com Minoca: registro de 126 pacientes em um hospital terciário de cardiologia / Clinical profile and incidence of cardiovascular events at 36 months in patients with Minoca: registry of 126 patients in a tertiary cardiology hospital

INTRODUÇÃO: Em 5% a 6% dos IAM não são observadas lesões obstrutivas maiores que 50%, sendo estes classificados como MINOCA (Infarto do Miocárdio com Artérias Coronárias não Obstrutivas). Estudos maiores de longo prazo demonstraram que o prognóstico desses pacientes não é benigno com risco aumentado de morte e novos eventos cardiovasculares. MÉTODOS: Nesta coorte de centro único, todos os pacientes que preencheram os critérios diagnósticos para MINOCA com (1) IAM (2) ausência de estenose coronária ≥ 50% na artéria relacionada ao infarto e (3) nenhuma outra causa específica clinicamente evidente entre março de 2000 e junho de 2022 foram incluídos com um acompanhamento médio de 30 (9,5-67,3) meses. As características da amostra foram descritas em frequências e valores medianos (p25%-p75%). A incidência de um novo evento cardiovascular (CV) em 36 meses após a MINOCA foi estimada pelo método de Kaplan-Meier e o teste de log-rank aplicado para comparar os grupos, acompanhado de intervalos de confiança de 95% e alfa de 5% (R 3,6,1 para MacOS). RESULTADOS: Dos 126 pacientes, 57,1% eram mulheres com cerca de 50 anos de idade (42,0-57,8). 20,6% tinham diabetes, 47,6% dislipidemia, 60,3% hipertensão e 20% IAM prévio. A apresentação clínica predominante foi IAMSSST (55,6%) e 7 pacientes tiveram um episódio de morte súbita abortada durante a internação. 38,1% dos pacientes não tiveram uma etiologia identificada. O mecanismo fisiopatológico mais prevalente foi ruptura da placa < 50% (16,7%), seguido de tromboembolismo (13,5%) e dissecção espontânea de coronária (13,5%). Apenas 3,2% realizaram tomografia de coerência óptica (OCT) ou ultrassom intravascular (IVUS). Nenhum teste provocativo foi realizado. 44,4% realizaram ressonância magnética cardíaca (RMC), com mediana de tempo para realização de 180,0 (60,0-707,5) dias após o evento. Em relação à medicação prescrita na alta hospitalar, 79,4% tiveram betabloqueador e IECA/BRA prescritos, 14,3% iniciaram anticoagulação e apenas 34,1% receberam dupla antiagregação plaquetária (DAP). A incidência do desfecho composto (morte CV, novo IAM, AVC e internação CV) em 36 meses foi de 15% (IC95% 8,9%-24,6%). A incidência de novo IAM foi de 6,3% (N=8), de AVC 2,4% (N=3), de hospitalização CV 17,5% (N=22) e apenas um óbito. CONCLUSÃO: Chama a atenção o risco do desfecho primário em 36 meses. Notavelmente, a maior parte da incidência foi atribuída à hospitalização CV. Um número importante de pacientes recebeu alta sem etiologia conhecida para sua apresentação clínica e, consequentemente, sem tratamento individualizado.

Experimental Arthritis Mouse Models Driven by Adaptive and/or Innate Inflammation.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease mainly affecting synovial joints. The clinical presentation of RA shows the heterogeneity of this disease with its underlying complex interactions between the innate and adaptive immune system and flare-ups of disease. Different disease models such as collagen induced arthritis, antigen induced arthritis, and Streptococcal cell wall induced arthritis can be exploited to investigate different aspects of the pathogenesis of arthritis. The disease can be monitored macroscopically over time via scoring systems. For histological examination, paraffin embedded knee sections can be used for hematoxylin and eosin staining to visualize cellular infiltration as well as for tartrate-resistant acid phosphatase (TRAP) staining to identify osteoclast-like cells. Cellular infiltration of the synovium by different myeloid cells such as tissue resident macrophages, dendritic cells and neutrophils can be monitored using flow cytometry. Here, we describe the methods for inducing the different mouse models for arthritis, including scoring systems per model, histological and flow cytometric analysis.

17beta-estradiol induces transthyretin expression in murine choroid plexus via an oestrogen receptor dependent pathway.

Oestrogen protects against AD by multiple mechanisms, including the enhancement of Abeta clearance. Transthyretin (TTR) is a homotetrameric protein mainly synthesized by the liver and choroid plexus (CP) of the brain that sequesters the amyloid beta (Abeta) peptide. In this study we examined the effects of 17beta-estradiol (E2) on TTR protein and mRNA levels, in primary cultures of rat CP epithelial cells (CPEC) by Western blot and Real Time PCR, respectively. Moreover, the localization of oestrogen receptors alpha (ERalpha) and beta (ERbeta) in response to E2 treatment was analysed by confocal microscopy in these cells. The expression of TTR, ERalpha and ERbeta was also compared in the CP of castrated female mice treated with E2 to vehicle-treated animals by Real Time PCR. TTR concentration in the CSF of all these animals was measured by radioimmunoassay. E2 treatment induced TTR transcription and increased TTR protein content in CPEC. Pre-treatment with ICI 182,780 (ICI) abrogated E2-induced TTR expression suggesting that, TTR is up-regulated via an ER-dependent pathway. Confocal microscopy demonstrated extranuclear ERalpha and ERbeta localization in untreated CPEC. Upon E2 treatment, translocation of ERalpha to the nucleus occurred, while ERbeta remained in the cytosol. These data was concurrent with the up-regulation of TTR expression detected in the CP of castrated female mice subjected to E2 treatment. Our results highlight the importance of E2 on the regulation of TTR, which may participate in the oestrogen-induced decrease in Abeta levels and deposition described in the literature.

5Alpha-dihydrotestosterone up-regulates transthyretin levels in mice and rat choroid plexus via an androgen receptor independent pathway.

Transthyretin (TTR) is a 55 kDa plasma homotetrameric protein mainly synthesized in the liver and choroid plexuses (CPs) of the brain that, functions as a carrier for thyroxin and retinol binding protein. It sequesters amyloid beta (Abeta) peptide, and TTR levels in the cerebrospinal fluid (CSF) appear to be inversely correlated with Alzheimer's disease (AD) onset and progression. Androgen deprivation increases plasma Abeta levels, which indicate that androgens may reduce the levels of soluble Abeta, the peptide widely implicated in the initiation of AD pathogenesis; however, the underlying mechanisms are still poorly understood. In this study we examined the effects of 5alpha-dihydrotestosterone (DHT) on TTR protein and mRNA levels, in primary cultures of rat CPs epithelial cells (CPEC) by Western blot, and real time PCR, respectively. Moreover, TTR concentrations were measured in the CSF of castrated wild-type, and transgenic mice expressing human TTR subjected to DHT treatment, by radioimmunoassay and ELISA, respectively. TTR mRNA expression was also compared in the CPs, of the animals from each experimental group by real time PCR. DHT treatment increased TTR protein levels in CPEC, and induced TTR transcription in these cells. The combination of flutamide with DHT in the treatment of CPEC did not abrogate DHT-induced TTR levels, suggesting that TTR is up-regulated via an androgen receptor independent pathway. In the CPs of both mice strains, DHT also increased TTR mRNA levels, but no significant differences in TTR protein levels were detected in the CSF of these animals. These findings open a wide range of possibilities for future studies on Abeta deposition and cognitive function, in response to androgen induction of TTR in animal models of AD.

Transthyretin is up-regulated by sex hormones in mice liver.

Misfolding and aggregation of mutated and wild-type transthyretin (TTR) can cause familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA), respectively. In some populations, FAP onset seems to occur on average 2-11 years earlier in men than in women, and SSA appears to be a disease of elderly men. Most (95-100%) SSA patients described in the literature are men, suggesting that amyloid deposition in these patients may be sex hormone related. On the basis of gender-related differences in FAP onset, and on the almost exclusivity of SSA in elder men, we hypothesize that, sex hormones may increase TTR synthesis by the liver, and therefore, may contribute to amyloid deposition. In order to test this hypothesis, castrated female and male mice were implanted with alzet mini-osmotic pumps, delivering 17beta-estradiol (E2) or 5alpha-dihydrotestosterone (DHT), or vehicle only, for 1 week. Sham operated animals were also included in the experiment. After hormonal stimulation, mice were euthanized under anaesthesia, and liver and sera were collected. The expression of TTR in liver, and the levels of TTR in sera in response to E2 and DHT were analysed by Real Time PCR and radioimmunoassay, respectively. Data analysis showed that, both hormones induced TTR transcription, which was concurrent with a consistent increase in the circulating levels of the protein. Taken together, all these data provide an indication that sex hormone stimulation may constitute a risk factor for SSA.

Measurement of plasma clotting time using ultrasonic shear waves.

This work presents a method that employs ultrasonic shear waves in the determination of prothrombin time (PT) and activated partial thromboplastin time (APTT), two plasma tests, during the coagulation process. Two AT-cut quartz crystal transducers are used as transmitter and receiver, with a frequency of 2.0 MHz. During the coagulation process there are random fluctuations in the amplitude of the wave transmitted through the sample of plasma that cease once the clot is formed. The time interval during which these fluctuations occur is used to indicate the coagulation time for the plasma. The method, repeated 35 times over the same plasma sample, provided for the mean of PT and APTT 12.7 s and 23.4 s with standard deviations of 0.8 s and 2.1 s, respectively. These results are in accordance with those obtained for normal plasma by means of other clinical tests.