Made available in DSpace on 2015-10-06T13:03:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-03-12. Added 1 bitstream(s) on 2015-10-06T13:18:58Z : No. of bitstreams: 1 000848488.pdf: 370380 bytes, checksum: 756f85f63eff42e05e06180956448b65 (MD5) / A insuficiência cardíaca congestiva (ICC) é uma síndrome que leva ao inadequado suprimento sanguíneo tecidual por disfunção do coração, e é tratada com a administração de furosemida em bolus intermitentes (BI). Entretanto, estudos em seres humanos com ICC demonstraram que a furosemida em taxa infusão contínua (TIC) apresenta maior eficácia e segurança em relação à administração em BI. Portanto, o objetivo deste estudo foi comparar a eficácia do diurético furosemida em TIC e BI em cães com degeneração mixomatosa valvar mitral. Para este fim, o estudo incluiu 20 cães, entre 8 e 12 anos, com peso entre 8 e 15 kg, e ICC classes Ia, Ib e II - ISACHC, e o grupo controle. Para o tratamento TIC, os cães receberam 0.66mg/kg IV furosemida como uma dose de carga seguida de 0.66mg/kg/h durante 8 horas. No tratamento BI os cães receberam 3 mg/kg IV furosemida na 0 e 4 horas. Os cães foram submetidos a tratamento por TIC e 15 dias mais tarde, os mesmos cães foram submetidos a tratamento por BI. Para ambos os tratamentos, foi administrado o mesmo volume de fluido e a produção de urina foi quantificada a cada hora. A ingestão hídrica, densidade urinária, pH urinário foram avaliados por hora. As variáveis sanguíneas, hematócrito (Ht), hemoglobina (Hb), creatinina (creat), ureia, proteína total (PT), albumina (alb) e os eletrólitos sódio (Na), potássio (K), magnésio (Mg), cálcio (Ca) e fosforo (P) foram avaliados a cada 2 horas. O peso e as variáveis ecocardiográficas foram avaliados antes e depois do tratamento. A produção urinaria por hora (mL/kg/h) e total (mL/kg/8h) foi superior no tratamento TIC em todos os animais (p<0,05). Os parâmetros ingestão hídrica, densidade urinária, diferença de pH urinário, diferença de peso, Ht, Hb, ureia, creat e fósforo junto com as diferenças das variáveis ecocardiográficas não apresentaram diferenças significativas entre os tratamentos (p>0,05). A furosemida... / Congestive heart failure (CHF) is a syndrome that leads to inadequate blood supply to the tissue due to heart dysfunction and is treated with furosemide in intermittent bolus (BI). However, studies in humans with CHF showed that furosemide continuous rate infusion (CRI) showed better efficacy and safety for the administration in BI. Therefore, the aim of this study was to compare the effectiveness of the diuretic furosemide in CRI and BI in dogs with mitral valve myxomatous degeneration. To this end, the study included 20 dogs between 8 and 12 years old, weighing between 8 and 15 kg, and ICC classes Ia, Ib and II - ISACHC, and the control group. CRI for the treatment, the dogs received 0.66mg/kg IV furosemide as a loading dose followed by 0.66mg/kg/h for 8 hours. BI treatment the dogs received 3 mg / kg IV furosemide at 0 and 4 hours. The dogs were treated by CRI and 15 days later, the same dogs were treated by BI. For both treatments, the same volume of fluid and urine production was quantitated was administered hourly. The water intake, urine specific gravity, urine pH were evaluated per hour. The variable blood, hematocrit (Hct), hemoglobin (Hb), creatinine (creat), urea, total protein (TP), albumin (ALB) and electrolytes sodium (Na), potassium (K), magnesium (Mg), calcium (Ca) and phosphorus (P) were evaluated every two hours. The weight and Doppler echocardiographic variables were evaluated before and after treatment. The urinary output per hour (mL/kg/h) and total (mL/kg/8h) was higher in the treatment CRI in the control group and CHF class II (p <0.05). The water intake, urine specific gravity, urinary pH difference, weight loss, Ht, Hb, urea, creat and phosphorus parameters along with the differences in Doppler echocardiographic variables were not significantly different between treatments (p> 0.05). The furosemide continuous infusion rate has increased urine output in dogs with MMVD functional classes Ia, Ib, II and ...

Orientador: Aparecido Antonio Camacho / Banca: Rosângela de Oliveira Alves Carvalho / Banca: Ronaldo Jun Yamato / Banca: Marlos Gonçalves de Souza / Banca: Júlio Carlos Canola / Resumo: A mensuração do volume atrial esquerdo (VAE) indexado a área de superfície corpórea (ASC) é obtido por meio do método biplanar de Simpson via ecocardiografia, e considerado um marcador prognóstico na avaliação da sobrecarga atrial esquerda nas cardiomiopatias e valvulopatias na medicina. Entretanto, nos cães com degeneração mixomatosa da válvula mitral (DMVM), valvulopatia caracterizada pela sobrecarga do átrio esquerdo (AE), a avaliação da sobrecarga atrial é realizada através da obtenção do diâmetro do AE e sua relação com o diâmetro da artéria Aorta (Ao) (AE:Ao), auxiliando na classificação da insuficiência cardíaca congestiva (ICC). Portanto, procurou-se mensurar os valores referentes ao VAE indexados à ASC de cães sadios e portadores da DMVM, utilizando o método biplanar de Simpson. Para isso, foram avaliados 107 cães sadios (controle) e 81 portadores da DMVM classes funcionais Ia, Ib e II da ICC (ISACHC), com o cálculo do VAE nos momentos da diástole (d) e sístole (s) atrial utilizando o método biplanar de Simpson. As imagens apicais quatro (4C) e duas câmaras (2C) foram obtidas por meio da ecocardiografia bidimensional via janela paraesternal esquerda (JPE) e direita (JPD) em todos os cães avaliados. Os valores referentes aos cães sadios foram correlacionados com o peso corporal utilizando o teste linear de Pearson e submetidos ao teste de normalidade estatística. Na comparação dos cães sadios com os portadores da DMVM, bem como entre as classes funcionais de ICC, utilizou-se análise de variância (ANOVA) e o teste de Tukey quando p<0,05. Os resultados demonstraram uma correlação alta e positiva das variáveis VAEd (r>0,77) e VAEs (r>0,73) com o peso corporal nos cães sadios, com posterior indexação dos valores na ASC e aprovação no teste de normalidade. Os valores obtidos utilizando a JPE e a JPD demonstraram diferenças significativas entre as janelas paraesternais. Já os cães ... / Abstract: The measurement of left atrial volume (LAV) indexed to body surface area ( ASC ) is obtained by the biplane Simpson method via echocardiography , and considered a prognostic marker in assessing left atrial cardiomyopathy and valvular heart disease in medicine . However , in dogs with myxomatous mitral valve (MMVD), valvular heart disease characterized by an overload of the left atrium (LA) , the assessment of atrial enlargement is accomplished by obtaining the LA diameter and its relation to the diameter of the aorta (Ao ) (LA:Ao) , assisting in the classification of congestive heart failure (CHF) . Therefore, we sought to measure the values for LAV indexed to ASC of healthy dogs and MMVD carriers using the biplane Simpson method. . Thus, 107 healthy dogs (control) and 81 patients with functional MMVD classes Ia, Ib and II of the CCI (ISACH) were evaluated by calculating the time of VAE in diastole (d) and systole (s) fibrillation using biplane Simpson's method. The framework (4C) and apical two-chamber images (2C) were obtained by two-dimensional echocardiography via left parasternal (JPE) in all dogs evaluated. The values for the healthy dogs were correlated with body weight using the Linear Test Pearson and submitted to statistical normality test. In comparison with healthy carriers of MMVD dogs, as well as between functional classes of ICC, we used analysis of variance (ANOVA) and Tukey's test at p<0.05. The results showed high positive correlation between LVAd (r>0.77) and LVAs (r > 0.73) variables with body weight in healthy dogs, with subsequent indexation of amounts on ASC and passing the normality test correlation. The values obtained using the JPE and JPD showed significant differences between the parasternal windows. The dogs with MMVD present significant differences (p<0.01) between functional classes Ib and II to the control group in LVAd/ASC ... / Doutor

Heart valve disease represents the second most common indication for cardiac surgery in the US, yet no therapy exists to slow down or revert its progression. Pharmacologic treatments are greatly in need for aortic and mitral valve disease and require a greater understanding of the underlying cellular mechanisms. Serotonin (5HT) dysfunction has been associated with heart valve disease, clinically observed in carcinoid syndrome or with the use of medications, such as the diet drug, Dexfenfluramine, a 5HT transporter (SERT) inhibitor and 5HT receptor (HTR) 2B agonist. Concurrently, Angiotensin II (AngII) and the renin-angiotensin system (RAS) greatly contribute to cardiac/valvular diseases. This dissertation explores the intersecting mechanisms by which 5HT and AngII contribute to aortic and mitral valve disease with an attempt to develop therapies to mitigate their progression. Three murine models were extensively utilized, mice lacking SERT (SERT KO) and wild-type mice receiving AngII infusion or Fluoxetine, a SERT inhibitor, with/without 5HTR2B inhibitors, to characterize histopathological, hemodynamic, and cellular level changes. Valvular interstitial cells (VICs) isolated from murine and human healthy valves were treated with various stressors known to be involved in valvular remodeling/5HT signaling, including 5HT, TGFβ1, AngII, and H2O2. Patients undergoing AV and MV surgery were prospectively enrolled in our study, with their valves isolated, genotyped for SERT promotor polymorphism, and studied for 5HT-related gene expression changes. We demonstrate that pathological, fibrotic thickening occurs to the AV and MV in response to AngII infusion, lack or inhibition of SERT in mice. AngII mice developed increased velocities and gradients across their AVs, a marker of hemodynamic compromised, and the cellular changes involved 5HT, TGFβ1 and other inflammatory pathways. Concurrent HTR2B blockade mitigated many of these changes. Most notably the MV in SERT KO mice demonstrated HTR2B upregulation and increasing levels of COL1A1. Both murine and human MVICs exposed to 5HT or TGFβ1 upregulated COL1A1, ACTA2 and/or HTR2B. Human AVICs treated with AngII in the setting of SERT downregulation displayed markers of osteogenic transdifferentiation, with these changes mitigated again by HTR2B blockade. Finally, patients with aortic stenosis and aortic insufficiency have lower levels of SERT than healthy patients, along with upregulation of various 5HT receptors. Presence of LL SERT promotor polymorphism is associated with faster progression of AI. We then further investigated the mechanisms by which SERT downregulation may enhance mitral and aortic valvulopathy by studying the activation of mechanically sensitive calcium channel, Piezo1, and the role of mechano-transduction. ScRNAseq results of both MR and MV cells demonstrated the presence of Piezo1 expression in different cell types on the mitral valve. Mitral valve interstitial cells in culture demonstrated Piezo1 Ca++ channel activity following administration of Yoda1, a Piezo1 agonist, with associated significant downregulation of SERT and diminished SERT function and upregulation of HTR2B. Taken together, this dissertation provides a novel and promising therapeutic target to mitigate aortic and mitral valve disease. Dysregulated AngII and 5HT, with SERT, HTR2B, and Piezo1 signaling, contribute to pathological remodeling to both valves, and preventing this signaling through Piezo1/HTR2B inhibition can prevent these changes.

Currently, mitral valve repair techniques have shown substandard mid-term and long term results. In order to improve the efficacy of these repair techniques, detailed knowledge of normal mitral valve function and the alterations to the valvular and subvalvular apparatus which occur under pathological conditions is required. Furthermore, current techniques may be optimized through a better understanding of the function and mechanics of the mitral valve after a particular repair. The experiments which comprise this study were designed using an in vitro approach since this technique has the clear advantage of isolating and independently controlling specific parameters that are of importance to valvular mechanics and function. The experiments were conducted in the Georgia Tech Left Heart Simulator using native porcine and human mitral valves. The first set of experiments measured the chordal force distribution and anterior leaflet strain of the mitral valve in its normal geometrical configuration. Subsequent experiments measure mitral regurgitation volume and chordal force distribution in conditions associated with ventricular dilation. The last set of experiments simulated two commonly used mitral repair techniques. For the Alfieri stitch experiments, the effects of mitral flow rate, transmitral pressure, and mitral annular area on valve stenosis, mitral regurgitation and Alfieri stitch force were evaluated. For annuloplasty, the effect of annular saddle curvature on anterior leaflet strain was quantified. In Conclusion, the normal geometry of the native mitral valve optimized its function and mechanics. Under pathological conditions associated with ventricular dilation, significant alterations to mitral valve function and mechanics were present. Although the studied repair techniques may have significantly restored valve function, severe alterations to the mechanics of the valve still persisted.