Hipertrofia do ventrículo direito por bandagem da artéria pulmonar em ratos. Estudo das alterações estruturais, funcionais e genéticas

Introduction: Right ventricular remodeling with consequent functional impairment may occur in some clinical conditions in adults and children. The triggering factors, the molecular mechanisms and the evolution are not yet well known. Left ventricular changes associated with right ventricular remodeling are also poorly understood. Objectives: Evaluate RV morphological, functional and gene expression parameters in rats submitted to pulmonary artery banding compared to control rats, as well as the temporal evolution of these parameters. • Analyze the influence of RV remodeling with pulmonary artery banding in rats and their controls on LV geometry, histology, gene expression and functional performance. Methods: Healthy 6-week-old male Wistar-EPM rats weighing 170 to 200 grams were included. One day after the echocardiogram, the animals underwent the procedure for BAP or not (control) and then randomly divided into subgroups according to the follow-up time: 72 hours, 2, 4, 6 or 8 weeks. In each subgroup were performed: new echocardiogram, hemodynamic study, collection of material for morphological analysis (hypertrophy and fibrosis) and molecular biology (gene expression). Results were presented as mean ± standard deviation of the mean. The comparison between variables of the subgroups and evolution times was made with two-way ANOVA and Tukey post-test. The adopted significance level was 5%. Results: There was no significant difference between subgroups in the percentage of water in the lung and liver (lung ranged from 76% to 78% and liver from 67% to 71%). The weight of the right chambers was significantly higher in animals with BAP in all subgroups (RV BAP from 0.34 to 0.48 g and controls from 0.17 to 0.20 g, AD with BAP from 0.09 to 0.14 g and controls from 0.02 to 0.03 g). In the RV of animals with BAP, there was a significant increase in myocyte nuclear volume (97 μm3 to 183.6 μm3) compared to controls (34.2 μm3 to 57.2 μm3), which were more intense in subgroups with lower exposure to BAP; and fibrosis percentage (5.9% to 10.4% vs 0.96% to 1.18%) was as higher as the BAP time was longer. At echocardiography there was also a significant increase in myocardial thickness in all groups with BAP (0.09 to 0.11 cm compared to controls- 0.04 to 0.05 cm), but without variation in RV diastolic diameter at echocardiography. From 2 to 8 weeks of BAP, the S 'wave (0.031 cm/s and 0.040 cm/s) and VPAVD (51% to 56%), RV systolic function parameters, were significantly lower than the respective controls (0,040 cm/s a 0,050cm/s; and 61% to 67%). Furthermore, higher expression of genes related to hypertrophy and extracellular matrix in the initial subgroups and apoptosis genes in the longer time subgroups of BAP were observed in RV. On the other hand, LV weight was not different between animals with or without BAP. The nuclear volume of the animals with BAP was larger than the controls (74 μm3 to 136 μm3; from 40.8 μm3 to 46.9 μm3); and the percentage of fibrosis was significantly higher in the 4- and 8-week BAP groups (1.2 and 2.2%) compared to the controls (0.4 and 0.7%). On echocardiography, the diastolic diameter and LV myocardial thickness were not different between animals with BAP and controls. Measurements of isovolumetric relaxation time and E-wave deceleration time on echocardiography were different between animals with BAP and controls in all subgroups, but there were no changes in diastolic function at hemodynamic study. There was also increased expression of genes related to various functions, in particular hypertrophy. Conclusion: 1) Rats submitted to pulmonary artery banding presented remodeling of RV compatible with hypertrophy. These alterations were mediated by increased expression of several genes and accompanied by functional alterations; coincident with the onset fibrosis. 2) Structural changes of the RV such as weight, myocardial thickness, myocyte nuclear volume and degree of fibrosis were modified according to the time of exposure to pulmonary artery banding and were related to variations in gene expression; Highlighting the change from alpha to beta pattern from early to late times. 3) The study suggests that the left ventricle developed histological alterations accompanied by modifications of gene expression simultaneously to the alterations found in the right ventricle.Introdução: O remodelamento do VD com consequente comprometimento funcional pode ocorrer em algumas condições clínicas em adultos e crianças. Os fatores desencadeadores, os mecanismos moleculares e a evolução não são ainda bem conhecidos. Também são pouco conhecidas as alterações do ventrículo esquerdo associadas com o remodelamento do VD. Objetivos: 1. Avaliar os parâmetros morfológicos, funcionais e de expressão gênica do ventrículo direito em ratos submetidos à bandagem da artéria pulmonar e a evolução temporal destes parâmetros. 2. Analisar a influência do remodelamento do ventrículo direito com BAP na geometria, histologia, expressão gênica e desempenho funcional do ventrículo esquerdo. Métodos: Foram incluídos ratos Wistar-EPM machos saudáveis com 6 semanas de vida e peso entre 170 e 200 gramas. Um dia após a realização do ecocardiograma os animais foram submetidos ao procedimento para BAP ou não (controle) e depois aleatoriamente divididos em subgrupos conforme o tempo de seguimento: 72 horas, 2, 4, 6 ou 8 semanas. Em cada subgrupo foram realizados: novo ecocardiograma, estudo hemodinâmico e coleta de material para análise morfológica (hipertrofia e fibrose) e de biologia molecular (expressão gênica). Os resultados foram apresentados como média ± desvio padrão da média; a comparação das variáveis entre os subgrupos e tempos de evolução foi feita com ANOVA duas vias e pós-teste de Tukey. O nível de significância adotado foi de 5%. Resultados: Não houve diferença significante entre os subgrupos no percentual de água no pulmão e no fígado (pulmão variou 76% a 78% e fígado de 67% a 71%). O peso das câmaras direitas foi significantemente maior nos animais com BAP em todos os subgrupos (VD BAP de 0,34 a 0,48 g e os controles de 0,17 a 0,20 g; AD com BAP de 0,09 a 0,14 g e nos controles de 0,02 a 0,03 g). No VD dos animais com BAP houve aumento significante do volume nuclear dos miócitos (97 μm3 a 183,6 μm3) comparado com controles (34,2 μm3 a 57,2 μm3), mais intensos nos subgrupos de menor exposição à BAP, e do percentual de fibrose (5,9% a 10,4% vs 0,96% a 1,18%), mais alto quanto maior o tempo de BAP. Ao ecocardiograma houve também aumento significante da espessura miocárdica em todos os grupos com BAP (0,09 a 0,11 cm em relação aos controles- 0,04 a 0,05cm), mas sem variação do diâmetro diastólico do VD ao ecocardiograma. De 2 a 8 semanas de BAP a onda S’ e de 0,031 cm/s a 0,040 cm/s) e a VPAVD (51% a 56 %), parâmetros de função sistólica do VD, foram significantemente menores em relação aos respectivos controles (0,040 cm/s a 0,050cm/s; e 61% a 67%). Foi observado no VD maior expressão de genes relacionados a hipertrofia e a matriz extracelular nos subgrupos iniciais e dos genes de apoptose nos subgrupos de maior tempo de BAP. O peso do VE não foi diferente entre os animais com ou sem BAP. O volume nuclear dos animais com BAP foram maiores que os controles (74 μm3 a 136 μm3; de 40,8 μm3 a 46,9 μm3). O percentual de fibrose foi significantemente maior nos grupos com 4 e 8 semanas de BAP (1,2 e 2,2%) em relação aos controles (0,4 e 0,7%). Ao ecocardiograma o diâmetro diastólico e a espessura miocárdica do VE não foram diferentes entre os animais com BAP e controles. As medidas do tempo de relaxamento isovolumétrico e do tempo de desaceleração da onda E ao ecocardiograma foram diferentes entre animais com BAP e controles em todos os subgrupos, mas não houve alterações da função diastólica ao estudo hemodinâmico. Houve também aumento da expressão de genes relacionados a diversas funções, em particular de hipertrofia. Conclusão: 1) Ratos submetidos a BAP apresentaram remodelamento do VD compatível com hipertrofia. Estas alterações foram mediadas por aumento da expressão de diversos genes e acompanhada de alterações funcionais; coincidentes com o surgimento de fibrose. 2) As variáveis estruturais do VD como peso, espessura miocárdica, volume nuclear do miócito e grau de fibrose, modificaram-se conforme o tempo de exposição à BAP e tiveram relação com variações na expressão gênica, destacando a mudança de padrão alfa para beta dos tempos iniciais para os mais tardios. 3) o estudo sugere que o VE desenvolveu alterações histológicas acompanhadas de modificações de expressão gênica simultâneas às alterações encontradas no VD.Dados abertos - Sucupira - Teses e dissertações (2019

Exercise Attenuates Renal Dysfunction with Preservation of Myocardial Function in Chronic Kidney Disease

Previous studies have suggested that exercise improves renal and cardiac functions in patients with chronic kidney disease. the aim of this study was to evaluate the effects of long-term aerobic swimming exercise with overload on renal and cardiac function in rats with 5/6 nefrectomy (5/6Nx). Eight Wistar rats were placed into 4 groups: Control (C), Control+Exercise (E), Sedentary 5/6Nx (NxS) and 5/6Nx+Exercise (NxE). the rats were subjected to swimming exercise sessions with overload for 30 min five days per week for five weeks. Exercise reduced the effect of 5/6Nx on creatinine clearance compared to the NxS group. in addition, exercise minimized the increase in mean proteinuria compared to the NxS group (96.9 +/- 10.0 vs. 51.4 +/- 9.9 mg/24 h; p<0.05). Blood pressure was higher in the NxS and NxE groups compared to the C and E groups (216 +/- 4 and 178 +/- 3 vs. 123 +/- 2 and 124 +/- 2 mm Hg, p<0.05). in the 200 glomeruli that were evaluated, the NxS group had a higher sclerosis index than did the NxE group (16% vs. 2%, p<0.05). Echocardiography demonstrated a higher anterior wall of the left ventricle (LV) in diastole in the NxS group compared with the C, E and NxE groups. the NxS group also had a higher LV posterior wall in diastole and systole compared with the E group. the developed isometric tension in Lmax of the heart papillary muscle was lower in the NxS group compared with the C, E and NxE groups. These results suggested that exercise in 5/6Nx animals might reduce the progression of renal disease and lessen the cardiovascular impact of a reduction in renal mass.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundacao Oswaldo Ramos (FOR)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, UNIFESP EPM, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Cardiophysiol & Pathophysiol Lab, São Paulo, BrazilUniv São Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP EPM, Dept Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Cardiophysiol & Pathophysiol Lab, São Paulo, BrazilWeb of Scienc

Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. the present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. the potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. in addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. the mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Nove Julho, UNINOVE, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, São Paulo, BrazilUniv São Paulo, Heart Inst InCor, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, São Paulo, BrazilCNPq: 477458/2009-2CNPq: 309715/2011-3CNPq: 479395/2012-8: 2009/54225-8Web of Scienc

Low-Level Laser Application in the Early Myocardial Infarction Stage Has No Beneficial Role in Heart Failure

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination. LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akti NEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.Conselho Nacional de Desenvolvimento Cientifico e TecnologicoFAPESPNove de Julho Univ, Lab Biophoton, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Lab Cardiac Physiol, Sao Paulo, SP, BrazilNove de Julho Univ, Program Med, Sao Paulo, BrazilUniv Sao Judas Tadeu, Brazil Phys Educ & Aging Sci Program, Translat Physiol Lab, Sao Paulo, BrazilUniv Fed Sao Paulo, Lab Cardiac Physiol, Sao Paulo, SP, BrazilCNPq: 4400851/2014-8FAPESP: 09-54225/8FAPESP: 15/11028-9Web of Scienc

Interação entre especialidades: miocardiopatia dilatada e neoplasia de mama HER2 positiva

O progresso no conhecimento dos mecanismos da doença e suas potenciais possibilidades de tratamento, têm com o incremento da pesquisa básica, trazido a algumas situações inusitadas. Como quando algo observado em uma situação específica, definida na prática clínica, pode ser transportado para o laboratório, instigando a investigação de uma provável terapêutica em uma doença não relacionada e fazendo o caminho inverso da "bench-to-bedside". Nos últimos anos, o uso de um anticorpo monoclonal, o trastuzumabe, mostrou-se imprescindível no tratamento das neoplasias de mama com amplificação/superexpressão de HER2, com ganho de sobrevida significativo nos contextos adjuvante e terapêutico. A observação da ocorrência de cardiotoxicidade induzida pelo trastuzumabe, assim como a identificação dos mecanismos relacionados a esse efeito colateral, possibilitaram a pesquisa desses mesmos fatores na miocardiopatia dilatada, de uma forma muito interessante

Digitoxin improves cardiovascular autonomic control in rats with heart failure

The effects of chronic treatment with digitoxin on arterial baroreceptor sensitivity for heart rate (HR) and renal sympathetic nerve activity (rSNA) control, cardiopulmonary reflex, and autonomic HR control in an animal model of heart failure were evaluated. Wistar rats were treated with digitoxin, which was administered in their daily feed (1mg/Kg/day), for 60 days. The following three experimental groups were evaluated: Sham, heart failure (HF), and HF treated with digitoxin (HF+DIG). We observed an increase in rSNA in the HF group (190±29pps,n=5) compared with the Sham group (98±14pps,n=5). Digitoxin treatment prevented an increase in rSNA (98±14pps,n=7). Therefore, arterial baroreceptor sensitivity was decreased in the HF group (-1.24±0.07bpm/mmHg,n=8) compared with the Sham group (-2.27±0.23bpm/mmHg,n=6). Digitoxin did not alter arterial baroreceptor sensitivity in the HF+DIG group. Finally, the HF group showed an increased low frequency band (LFb: 23±5ms2,n=8) and a decreased high frequency band (HFb: 77±5ms2,n=8) compared with the Sham group (LFb: 14±3ms2; HFb: 86±3ms2,n=9); the HF+DIG group exhibited normalized parameters (LFb: 15±3ms2;HFb: 85±3ms2,n=9). In conclusion, the benefits of decreasing rSNA are not directly related to improvements in peripheral cardiovascular reflexes; such occurrences are due in part to changes in the central nuclei of the brain responsible for autonomic cardiovascular control.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

Objective: An unclear issue is whether gender may influence at cardiac remodeling after myocardial infarction (MI). We evaluated left ventricle remodeling in female and male rats post-MI. Methods: Rats were submitted to anterior descending coronary occlusion. Echocardiographic evaluations were performed on the first and sixth week post-occlusion to determine myocardial infarction size and left ventricle systolic function (FAC, fractional area change). Pulsed Doppler was applied to analyze left ventricle diastolic function using the following parameters: E wave, A wave, E/A ratio. Two-way ANOVA was applied for comparisons, complemented by the Bonferroni test. A P≤=0.05 was considered significant. Results: There were no significant differences between genders for morphometric parameters on first (MI [Female (FE): 44.0±5.0 vs. Male (MA): 42.0±3.0%]; diastolic [FE: 0.04±0.003 vs. MA: 0.037±0.005, mm/g] and systolic [FE: 0.03±0.0004 vs. MA: 0.028±0.005, mm/g] diameters of left ventricle) and sixth (MI [FE: 44.0±5.0 vs. MA: 42.0±3.0, %]; diastolic [FE: 0.043±0.01 vs. MA: 0.034±0.005, mm/g] and systolic [FE: 0.035±0.01 vs. MA: 0.027±0.005, mm/g] of LV) week. Similar findings were reported for left ventricle functional parameters on first (FAC [FE: 34.0±6.0 vs. MA: 32.0±4.0, %]; wave E [FE: 70.0±18.0 vs. MA: 73.0±14.0, cm/s]; wave A [FE: 20.0±12.0 vs. MA: 28.0±13.0, cm/s]; E/A [FE: 4.9±3.4 vs. MA: 3.3±1.8]) and sixth (FAC [FE: 29.0±7.0 vs. MA: 31.0±7.0, %]; wave E [FE: 85.0±18.0 vs. MA: 87.0±20.0, cm/s]; wave A [FE: 20.0±11.0 vs. MA: 28.0±17.0, cm/s]; E/A [FE: 6.2±4.0 vs. MA: 4.6±3.4]) week. Conclusion: Gender does not influence left ventricle remodeling post-MI in rats

A SINGLE LOW-LEVEL LASER APPLICATION REDUCES MYOCARDIAL INFARCTION SIZE, IMPROVES CARDIAC PERFORMANCE AND ATTENUATES APOPTOSIS IN REMOTE MYOCARDIUM

Nove de Julho Univ, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Heart, Rua Botucatu 862, BR-04023062 Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Heart, Rua Botucatu 862, BR-04023062 Sao Paulo, BrazilWeb of Scienc