Heart Transplantation for Peripartum Cardiomyopathy: A Single-Center Experience / Transplante Cardíaco por Cardiomiopatia Periparto: Uma Experiência de Centro Único

Abstract Background: Peripartum cardiomyopathy is an idiopathic disorder defined by the occurrence of acute heart failure during late pregnancy or post-partum period in the absence of any other definable cause. Its clinical course is variable and severe cases might require heart transplantation. Objective: To investigate long-term outcomes after heart transplantation (HT) for peripartum cardiomyopathy (PPCM). Methods: Out of a single-center series of 1938 HT, 14 HT were performed for PPCM. We evaluated clinical characteristics, transplant-related complications, and long-term outcomes, in comparison with 28 sex-matched controls. Primary endpoint was death from any cause; secondary endpoints were transplant-related complications (rejection, infection, cardiac allograft vasculopathy). A value of p < 0.05 was considered of statistical significance. Results: PPCM patients and matched controls were comparable for most variables (all p values > 0.05), except for a higher use of inotropes at the time of HT in PPCM group (p = 0.03). During a median follow-up of 7.7 years, 16 patients died, 3 (21.5%) in PPCM group and 13 (46.5%) in control group. Mortality was significantly lower in PPCM group (p = 0.03). No significant difference was found in terms of transplant-related complications (p > 0.05). Conclusions: Long-term outcomes following HT for PPCM are favorable. Heart transplantation is a valuable option for PPCM patients who did not recover significantly under medical treatment.

Resumo Fundamento: A cardiomiopatia periparto é uma doença idiopática definida pela ocorrência de insuficiência cardíaca aguda durante a gravidez tardia ou pós-parto na ausência de qualquer outra causa definível. Seu curso clínico é variável e casos graves podem exigir transplante. cardíaco. Objetivo: Pesquisar os resultados a longo prazo após transplante cardíaco (TC) por cardiomiopatia periparto (CMPP). Métodos: De uma única série central de 1938 TC, 14 TC foram realizados por CMPP. Foram avaliadas características clínicas, complicações relacionadas ao transplante e resultados a longo prazo, em comparação com 28 controles pareados por gênero. O principal critério de avaliação foi a morte por qualquer causa; os critérios secundários foram complicações relacionadas ao transplante (rejeição, infecção, vasculopatia do aloenxerto cardíaco). Um valor de p < 0,05 foi considerado estatisticamente significante. Resultados: As pacientes com CMPP e controles pareados foram comparáveis ​​para a maioria das variáveis (todos os valores de p > 0,05), exceto para um maior uso de inotrópicos no momento do TC no grupo CMPP (p = 0,03). Durante um seguimento médio de 7,7 anos, 16 pacientes morreram, 3 (21,5%) no grupo CMPP e 13 (46,5%) no grupo controle. A mortalidade foi significativamente menor no grupo CMPP (p = 0,03). Não foram encontradas diferenças significativas em termos de complicações relacionadas ao transplante (p> 0,05). Conclusões: Os resultados a longo prazo após TC para CMPP são favoráveis. O transplante cardíaco é uma opção valiosa para pacientes com CMPP que não se recuperaram significativamente sob tratamento médico.

Inflammation and oxidative stress in heart failure: effects of exercise intensity and duration

Although acute exercise is apparently pro-inflammatory and increases oxidative stress, it can promote the necessary stress stimulus to train chronic adaptations in patients with chronic heart failure (CHF). This study aimed to compare the effects of exercise intensity and duration on the inflammatory markers soluble tumor necrosis factor receptor (sTNFR1) and interleukin-6 (IL-6), and on oxidative stress [malondialdehyde (MDA) and antioxidant enzymes: catalase (CAT) and superoxide dismutase (SOD)] in individuals with CHF. Eighteen patients performed three exercise sessions: 30 min of moderate-intensity (M30) exercise, 30 min of low-intensity (L30) exercise, and 45 min of low-intensity (L45) exercise. Blood analysis was performed before exercise (baseline), immediately after each session (after), and 1 h after the end of each session (1h after). Thirty min of M30 exercise promoted a larger stressor stimulus, both pro-inflammatory and pro-oxidative, than that promoted by exercises L30 and L45. This was evidenced by increased sTNFR1 and MDA levels after exercise M30. In response to this stressor stimulus, 1 h after exercise, there was an increase in IL-6 and CAT levels, and a return of sTNFR1 to baseline levels. These findings suggest that compared with the duration of exercise, the exercise intensity was an important factor of physiologic adjustments.

A Comparison of the Bleaching Effectiveness of Chlorine Dioxide and Hydrogen Peroxide on Dental Composite

This study was carried out to verify if composites could be bleached using chlorine dioxide as compared with hydrogen peroxide. 3M ESPE Filtek Z350 Universal Restorative discs were prepared (n=40), with dimensions 5 mm diameter x 2 mm thickness. The discs were divided into 4 groups of 10 discs each. Color assessment was performed by CIEDE2000. The discs were stained with coffee, tea, wine and distilled water (control) solutions for 14 days, 5 hours daily. Color assessment was repeated on stained discs and followed by bleaching of 5 discs from each group using chlorine dioxide and hydrogen peroxide in-office systems. Finally, a last color assessment was performed and compared statistically. DE2000 after bleaching was very close to baseline for both the bleaching agents, although chlorine dioxide showed better results than hydrogen peroxide. After staining, there was a clinically significant discoloration (∆E2000≥3.43) for the tea, coffee and wine groups, and discoloration (∆E2000) was seen more in the wine group as compared to tea and coffee. Overall, the control group (distilled water) had the least color change in the three intervals. After bleaching, the color in all specimens returned close to the baseline. The color differences between bleaching and baseline were less than 3.43 for all groups. The obtained results show that chlorine dioxide is slightly superior to hydrogen peroxide in the bleaching of composites, while maintaining the shade of the composite close to the baseline.

Este estudo foi realizado para verificar se resinas compostas podem ser clareadas com uso do dióxido de cloro, em comparação com peróxido de hidrogênio. Foram preparados discos com resina restauradora Filtek Z350 3M ESPE (n=40), com dimensões 5 mm de diâmetro × 2 mm de espessura. Os discos foram divididos em 4 grupos de 10 discos cada. A avaliação da cor foi realizada por meio do CIEDE2000. Os discos foram manchados com soluções de café, chá, vinho e água destilada (controle) por 5 h diárias durante 14 dias. A avaliação da cor foi repetida nos discos manchados e seguida por clareamento de 5 discos de cada grupo, utilizando dióxido de cloro ou peróxido de hidrogênio pela técnica de consultório. Finalmente, uma última avaliação da cor foi realizada e as técnicas comparadas estatisticamente. DE2000 após o clareamento foi muito próxima ao baseline, para ambos os agentes clareadores, embora o dióxido de cloro tenha mostrado melhores resultados do que o peróxido de hidrogênio. Após o manchamento, houve uma descoloração clinicamente significativa (ΔE2000≥3,43) para os grupos de chá, café e vinho, sendo que o clareamento (ΔE2000) foi melhor obtido com o grupo do vinho, em comparação com chá e café. No geral, o grupo controle (água destilada) teve a menor mudança de cor nos três intervalos. Após o clareamento, a cor em todos os espécimes voltou próxima ao baseline. As diferenças de cor entre o clareamento e o baseline foram inferiores a 3,43 para todos os grupos. Os resultados indicam que o dióxido de cloro é ligeiramente superior ao peróxido de hidrogênio no clareamento de resinas compostas, mantendo a cor próxima à escala do baseline.

An antibody reactive to the Gly63-Lys68 epitope of NT-proBNP exhibits O-glycosylation-independent binding

The N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP) is a commonly used biomarker for the diagnosis of congestive heart failure, although its biological function is not well known. NT-proBNP exhibits heavy O-linked glycosylation, and it is quite difficult to develop an antibody that exhibits glycosylation-independent binding. We developed an antibody that binds to the recombinant NT-proBNP protein and its deglycosylated form with similar affinities in an enzyme immunoassay. The epitope was defined as Gly63-Lys68 based on mimetic peptide screening, site-directed mutagenesis and a competition assay with a peptide mimotope. The nearest O-glycosylation residues are Thr58 and Thr71; therefore, four amino acid residues intervene between the epitope and those residues in both directions. In conclusion, we report that an antibody reactive to Gly63-Lys68 of NT-proBNP exhibits O-glycosylation-independent binding.

Cardiac gene expression and systemic cytokine profile are complementary in a murine model of post-ischemic heart failure

After myocardial infarction (MI), activation of the immune system and inflammatory mechanisms, among others, can lead to ventricular remodeling and heart failure (HF). The interaction between these systemic alterations and corresponding changes in the heart has not been extensively examined in the setting of chronic ischemia. The main purpose of this study was to investigate alterations in cardiac gene and systemic cytokine profile in mice with post-ischemic HF. Plasma was tested for IgM and IgG anti-heart reactive repertoire and inflammatory cytokines. Heart samples were assayed for gene expression by analyzing hybridization to AECOM 32k mouse microarrays. Ischemic HF significantly increased the levels of total serum IgM (by 5.2-fold) and total IgG (by 3.6-fold) associated with a relatively high content of anti-heart specificity. A comparable increase was observed in the levels of circulating pro-inflammatory cytokines such as IL-1â (3.8X) and TNF-á (6.0X). IFN-ã was also increased by 3.1-fold in the MI group. However, IL-4 and IL-10 were not significantly different between the MI and sham-operated groups. Chemokines such as MCP-1 and IL-8 were 1.4- and 13-fold increased, respectively, in the plasma of infarcted mice. We identified 2079 well annotated unigenes that were significantly regulated by post-ischemic HF. Complement activation and immune response were among the most up-regulated processes. Interestingly, 21 of the 101 quantified unigenes involved in the inflammatory response were significantly up-regulated and none were down-regulated. These data indicate that post-ischemic heart remodeling is accompanied by immune-mediated mechanisms that act both systemically and locally.

Ativação imune-inflamatória na insuficiência cardíaca / Immune-inflammatory activation in heart failure

Apesar de relativamente recente, nota-se um acúmulo crescente e robusto de evidências experimentais e clínicas que apontam um estado gradativo de ativação imune-inflamatória em pacientes com insuficiência cardíaca (IC). Níveis elevados de diversas citocinas são encontrados na circulação e no músculo cardíaco de indivíduos com IC, correlacionando-se, invariavelmente, com o grau de gravidade da doença e agindo na disfunção endotelial, no estresse oxidativo, na indução de anemia, na apoptose miocitária e na perda gradativa de massa muscular esquelética - no que se convencionou denominar o paradigma inflamatório da IC. Não só o miocárdio, mas diversos tecidos parecem sintetizar tais citocinas e perpetuar esse contínuo estado de inflamação em baixo grau, inclusive leucócitos, monócitos, células musculares esqueléticas e endoteliais - em resposta a estímulos hemodinâmicos, infecciosos, à hipóxia, ao estresse oxidativo e à ativação neuro-humoral, entre outros. Desse modo, forma-se uma rede de moléculas que interagem entre si, estabelecendo, ainda, conexões com outros eixos que efetivamente contribuem para a deterioração clínica dos pacientes - o que se encaixa no modelo fisiopatológico de acometimento multissistêmico que tem sido cada vez mais atribuído à IC. Ainda que a dosagem periférica desses biomarcadores reúna evidências bastante sólidas de poder prognóstico, os resultados dos ensaios terapêuticos que modularam em fase clínica a alça imune-inflamatória foram, até então, pouco encorajadores. Desse modo, acreditamos que é fundamental compreender melhor a ativação inflamatória e sua multifacetada relação com os eixos de descompensação da doença, para que possamos estabelecer novas perspectivas terapêuticas com impacto de relevância em um futuro próximo.

Despite being relatively recent, a growing and significant accumulation of experimental and clinical evidence has been observed that points to a gradual state of immune-inflammatory activation in patients with heart failure (HF). High levels of several cytokines are found in the circulation and cardiac muscle of individuals with HF, and invariably correlate with the severity of the disease. These cytokines act on endothelial dysfunction, oxidative stress, induction of anemia, myocyte apoptosis, and on the progressive loss of skeletal muscle mass - which is conventionally called the inflammatory paradigm of HF. Not only the myocardium, but also several tissues seem to synthesize these cytokines and perpetuate this continuous inflammatory state at a low degree, including leukocytes, monocytes, skeletal muscle cells and endothelial cells - in response to hemodynamic and infectious stimuli, to hypoxia, to oxidative stress, to neurohumoral activation, and others. Thus, a network of molecules that interact with each other is formed, and connections with other axes that effectively contribute to the clinical deterioration of the patients are also established - which fits into the pathophysiological model of multisystemic involvement that has been increasingly attributed to HF. Although the determination of these biomarkers in peripheral blood provides solid evidence of prognostic power, the results of therapeutic trials that modulated the immune-inflammatory loop in the clinical phase have been, so far, hardly encouraging. Therefore, we believe that a better understanding of the inflammatory activation and its multifaceted relation with the axes of decompensation of the disease is key for new therapeutic perspectives with a relevant impact to be established in the near future.