Background:  The right ventricle (RV) is multi-compartmental in orientation with a complex structural geometry. However, assessment of this part of the heart has remained an elusive clinical challenge. As a matter of fact, its importance has been underestimated in the past, especially its role as a determinant of cardiac symptoms, exercise capacity in chronic heart failure and survival in patients with valvular disease of the left heart. Evidence also exists that pulmonary hypertension (PH) affects primarily the right ventricular function. On the other hand, previous literature suggested that severe aortic stenosis (AS) affects left ventricular (LV) structure and function which partially recover after aortic valve replacement (AVR). However, the impact of that on RV global and segmental function remains undetermined.  Objectives: We sought to gain more insight into the RV physiology using 3D technology, Speckle tracking as well as already applicable echocardiographic measures. Our first aim was to assess the normal differential function of the RV inflow tract (IT), apical and outflow tract (OT) compartments, also their interrelations and the response to pulmonary hypertension. We also investigated the extent of RV dysfunction in severe AS and its response to AVR. Lastly, we studied the extent of global and regional right ventricular dysfunction in patients with pulmonary hypertension of different aetiologies and normal LV function. Methods: The studies were performed on three different groups; (1) left sided heart failure with (Group 1) and without (Group 2) secondary pulmonary hypertension, (2) severe aortic stenosis and six months post AVR and (3) pulmonary hypertension of different aetiologies and normal left ventricular function. We used 3D, speckle tracking echocardiography and conventionally available Doppler echocardiographic transthoracic techniques including M-mode, 2D and myocardial tissue Doppler. All patients’ measurements were compared with healthy subjects (controls). Statistics were performed using a commercially available SPSS software. Results: 1-  Our RV 3D tripartite model was validated with 2D measures and eventually showed strong correlations between RV inflow diameter (2D) and end diastolic volume (3D) (r=0.69, p<0.001) and between tricuspid annular systolic excursion (TAPSE) and RV ejection fraction (3D) (r=0.71, p<0.001). In patients (group 1 & 2) we found that the apical ejection fraction (EF) was less than the inflow and outflow (controls:  p<0.01 & p<0.01, Group 1:  p<0.05 & p<0.01 and Group 2: p<0.05 & p<0.01, respectively). Ejection fraction (EF) was reduced in both patient groups (p<0.05 for all compartments). Whilst in controls, the inflow compartment reached the minimum volume 20 ms before the outflow and apex, in Group 2 it was virtually simultaneous. Both patient groups showed prolonged isovolumic contraction (IVC) and relaxation (IVR) times (p<0.05 for all). Also, in controls, the outflow tract was the only compartment where the rate of volume fall correlated with the time to peak RV ejection (r = 0.62, p = 0.03). In Group 1, this relationship was lost and became with the inflow compartment (r = 0.61, p = 0.01). In Group 2, the highest correlation was with the apex (r=0.60, p<0.05), but not with the outflow tract. 2- In patients with severe aortic stenosis, time to peak RV ejection correlated with the basal cavity segment (r = 0.72, p<0.001) but not with the RVOT. The same pattern of disturbance remained after 6 months of AVR (r = 0.71, p<0.001). In contrast to the pre-operative and post-operative patients, time to RV peak ejection correlated with the time to peak outflow tract strain rate (r = 0.7, p<0.001), but not with basal cavity function. Finally in patients, RVOT strain rate (SR) did not change after AVR but basal cavity SR fell  (p=0.04). 3- In patients with pulmonary hypertension of different aetiologies and normal LV function, RV inflow and outflow tracts were dilated (p<0.001 for both). Furthermore, TAPSE (p<0.001), inflow velocities (p<0.001), basal and mid-cavity strain rate (SR) and longitudinal displacement (p<0.001 for all) were all reduced. The time to peak systolic SR at basal, mid-cavity (p<0.001 for both) and RVOT (p=0.007) was short as was that to peak displacement (p<0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r=0.7, p<0.001) in controls, but with that of the mid cavity in patients (r=0.71, p<0.001). Finally, pulmonary ejection acceleration (PAc) was faster (p=0.001) and RV filling time shorter in patients (p=0.03) with respect to controls. Conclusion: RV has distinct features for the inflow, apical and outflow tract compartments, with different extent of contribution to the overall systolic function. In PH, RV becomes one dyssynchronous compartment which itself may have perpetual effect on overall cardiac dysfunction. In addition, critical aortic stenosis results in RV configuration changes with the inflow tract, rather than outflow tract, determining peak ejection. This pattern of disturbance remains six month after valve replacement, which confirms that once RV physiology is disturbed it does not fully recover. The findings of this study suggest an organised RV remodelling which might explain the known limited exercise capacity in such patients. Furthermore, in patients with PH of different aetiologies and normal LV function, there is a similar pattern of RV disturbance. Therefore, we can conclude that early identification of such changes might help in identifying patients who need more aggressive therapy early on in the disease process.

Background: Aortic stenosis (AS) is the most common heart valve disease in Europe and North America. Age-related calcification of the valve is the commonest cause of acquired AS, especially in patients older than 70 years.Conventional surgical aortic valve replacement (SAVR) and the novel, minimally invasive transcatheter aortic valve implantation (TAVI), effectively preserve left ventricular (LV) function, relieve symptoms and improve survival in patients with severe symptomatic AS. However, patients with impaired LV function may carry significant operative risk, and long recovery time. In addition, such patients might have other comorbidities, and hence adding another challenge. Thus evaluation of ventricular function before and after AVR, as well as critical evaluation of TAVI patients should contribute to better clinical outcome. Methods: We studied LV function by conventional echocardiography before and after SAVR in the following groups; (I) 86 patients (aged 71±10 years) with severe AS and LV dysfunction; (II) 112 consecutive elderly AS patients (aged 77±2 years) and compared them with 72 younger patients (aged 60±1 years); (III)66 patients (age 70±2 years, 53 male) who underwent AVR for severe AS with concurrent LV dysfunction; (IV) 89 consecutive patients with symptomatic severeAS who underwent successful TAVI, 45 of whom received trans-apical TAVI (TA)(age 80.8±4.9 year, 26 male) and 44 trans-femoral TAVI (TF) (age 82.9±5.8 year,22 male).The conventional echocardiographic measurements were made according to the guidelines. Severe AS was identified by aortic valve mean pressure gradient >40mmHg or valve area <1.0 cm2. LV systolic dysfunction was identified as ejection fraction (EF) <50%. LV long-axis function was presented by mitral annular plane systolic excursion ( MAPSE ) at lateral wall and septal wall, which were measured from apical four-chamber view. Also from the same view, LV septal and lateral wall deformation using STE as well as global longitudinal systolic strain. The LV systolic twist as the net difference between apical rotation and basal rotation was measured from the parasternal apical and basal short-axis views in the TAVI patients. Results: Study I: In the low flow and high gradient group, operative (30-day) mortality was 10%, and peri-operative mortality was associated with lower mean LVEF, higher mitral E:A ratio, peak systolic pulmonary artery pressure (PSPAP), and higher serum creatinine (all p<0.001), NYHA class III–IV, concomitant coronary artery bypass graft (CABG), urgent surgery, and longer bypass-time (all p< 0.05). Mortality at 4 years was 17%. Univariate predictors of 4-year mortality were: lower EF (p<0.001), presence of restrictive LV filling (p<0.001), raised PSPAP (p<0.001) and CABG (p=0.037). However, only EF<40 % (p=0.03), the presence of restrictive LV filling (p=0.033) and raised PSPAP (p<0.01)independently predicted mortality in this group.Study II: Elderly patients had higher NYHA class, more frequent atrial fibrillation (AF), coronary artery disease (CAD), emergency operation and use of bioprosthetic valves. They also had shorter E-wave deceleration time (DT) and larger left atria (LA) (p<0.05 for all). 30-day mortality was 12% vs 4 % (Log Rank x2=3.02, p=0.08) and long term mortality was 18% vs 7% (Log Rank x2=4.38,p=0.04) in the two groups, respectively. Age was not related to mortality after adjustment for other variables. Among all variables, anemia (OR 4.20, CI:1.02–6.86, p=0.04), cardiopulmonary bypass (CPB) time (OR 1.02, CI 1.01–1.04,p<0.01), significant patient prosthesis mismatch (PPM) (OR 5.43, CI 1.04–18.40,p<0.05) were associated with 30-day mortality in elderly patients. Their long-term mortality was related to CBP time (OR 1.02, CI 1.00–1.05, p=0.04),PPM (OR 4.64, CI 1.33–16.11, p=0.02) and raised LA pressure: DT (OR 0.94, CI0.84–0.99, p=0.03) and pulmonary artery systolic pressure (PASP) (OR 1.12, CI1.03–1.19, p<0.001).STUDY III: Following SAVR peak aortic pressure gradient (AOPG) decreased and indexed valve area increased (64±3 to 19±1 mmHg and 0.30±0.01 to 0.89±0.03 cm2/m2, p<0.001 for both). LVEF increased (from 45±1 to 54±2%;p<0.001), LV end diastolic and end-systolic dimensions fell (LVEDD index: from 33±1 to 30±1 mm/m2; and LVESD index: from 27±1 to 20±1 mm/m2; (p<0.01 forboth). LV diastolic dysfunction improved as evidenced by the fall in E/A ratio (from 2.6±0.2 to 1.9±0.4) and prolongation of total filling time; (from 29.2±0.6 to31.4±0.5 s/min, p=0.01 for both). Among all echocardiographic variables, LV dimensions (LVEDD index, OR 0.70, CI 0.52–0.97, p<0.05; LVESD index, OR 0.57, CI 0.40–0.85, p=0.005) were the two independent predictors of post-operative LV functional recovery on multivariate analysis. A cut-off value ofpre-operative LVESD index<=27.5 mm/m2 was 85% sensitive and 72% specific inpredicting intermediate-term recovery of LV function after AVR (AUC, 0.72, p=0.002). STUDY IV: Before TAVI, there was no difference between the two patient groups in gender, age, body surface area (BSA) and baseline LV function. However, left ventricular mass index (LVMi), left atrial volume index (LAVi) and tricuspid regurgitation pressure drop (TRPdrop) were increased in the TA group (p<0.05).One week after TAVI, aortic pressure gradient (AOPG) markedly dropped in thetwo groups (both p<0.001), LVEDD index and LVESD index fell but EF andmyocardial strain remained unchanged. Overall cavity twist reduced (p<0.048).Significant LVESD index reduction was only seen in TF group (p=0.02) with a slight increase in LVEF (p=0.04). Lateral MAPSE increased only in the TF group(p=0.02). LV longitudinal systolic strain remained unchanged in TA patients while apical lateral strain increased in TF group. LV apical rotation fell in the two groups but basal rotation increased only in the TA patients (p=0.02). LAVi reduced in bothgroups and to a greater extent in TF TAVI (p=0.006), as did TRPdrop (p<0.001). Conclusion: SAVR and TAVI are two effective treatments for severe AS patients.The severity of pre-operative systolic and diastolic LV dysfunction is the major predictor of mortality following SAVR for low-flow and high gradient AS.Peri-operative AVR survival is encouraging in the elderly. Long term mortality in the elderly is related to PPM, LV diastolic dysfunction and secondary pulmonary hypertension. LV functional recovery was evident in most patients with LV dysfunction after SAVR. A lower prevalence of LV functional recovery in patients with large pre-operative LVESD index might signify the loss of contractile reserveand thus predict post-operative functional recovery. TAVI results in significant early improvement of segmental and overall ventricular function, particularly in patients receiving the trans-femoral approach. The delayed recovery of the trans-apical TAVI group, we studied, might reflect worse pre-procedural diastolic cavity function.

<p>Härtill 5 uppsatser</p> / digitalisering@umu

Background：Aortic stenosis (AS) is the commonest valve disease in the West. Aortic valve replacement (AVR) remains the only available management for AS and results in improved symptoms and recovery of ventricular functions. In addition, it is well known that AVR results in disruption of LV function mainly in the form of reversal of septal motion as well as depression of right ventricular (RV) systolic function. The aim of this thesis was to study, in detail, the early and mid-term response of ventricular function to AVR procedures (surgical and TAVI) as well as post operative patients’ exercise capacity. Methods：We studied LV and RV function by Doppler echocardiography and speckle tracking echocardiography (STE) in the following 4 groups; (1) 30 severe AS patients (age 62±11 years, 19 male) with normal LV ejection fraction (EF) who underwent AVR, (2) 20 severe AS patients (age 79±6 years, 14 male) who underwent TAVI, (3) 30 healthy controls (age 63±11 years, 16 male), (4) 21 healthy controls (age 57±9 years, 14 male) who underwent exercise echocardiography. Results: After one week of TAVI, the septal radial motion and RV tricuspid annulus peak systolic excursion (TAPSE) were not different from before, while surgical AVR had significantly reversed septal radial motion and TAPSE dropped by 70% compared to before. The extent of the reversed septal motion correlated with that of TAPSE (r=0.78, p&lt;0.001) in the patients as a whole after AVR and TAVI (Study I). Compared with controls, the LV twist function was increased in AS patients before and normalized after 6 months of surgical AVR. In controls, the LV twist correlated with LV fractional shortening (r=0.81, p&lt;0.001), a relationship which became weak in patients before (r=0.52, p&lt;0.01) and after AVR (r=0.34, p=ns) (Study II). After 6 months of surgical AVR, the reversed septal radial motion was still significantly lower than before. The septal peak displacement also decreased and its time became prolonged. In contrast, the LV lateral wall peak displacement increased and the time to peak displacement was early. The accentuated lateral wall peak displacement correlated with the septal peak displacement time delay (r=0.60, p&lt;0.001) and septal-lateral time delay (r=0.64, p&lt;0.001) (Study III). In 21 surgical AVR patients who performed exercise echocardiography, the LV function was normal at rest but different from controls with exercise. At peak exercise, oxygen consumption (pVO2) was lower in patients than controls. Although patients could achieve cardiac output (CO) and heart rate (HR) similar to controls at peak exercise, the LV systolic and early diastolic myocardial velocities and strain rate as well as their delta changes were significantly lower than controls. pVO2 correlated with peak exercise LV myocardial function in the patients group only, and the systolic global longitudinal strain rate (GLSRs) at peak exercise was the only independent predictor of pVO2 in multivariate regression analysis (p=0.03) (Study IV). Conclusion: Surgical AVR is an effective treatment for AS patients, but results in reversed septal radial motion and reduced TAPSE. The newly developed TAVI procedure maintains RV function which results in preservation of septal radial motion. In AS, the LV twist function is exaggerated, normalizes after AVR but loses its relationship with basal LV function. While the reversed septal motion results in decreased and delayed septal longitudinal displacement which is compensated for by the accentuated lateral wall displacement and the time early. These patients remain suffering from limited exercise capacity years after AVR.

Orientador: Antonio Carlos Cicogna / Resumo: Introdução - A estenose aórtica supravalvar (EAo) experimental é utilizada para induzir a remodelação cardíaca (RC) patológica; esse modelo provoca, inicialmente disfunção diastólica e, posteriormente, distúrbio sistólico e insuficiência cardíaca (IC). Diferentes fatores podem contribuir para essa alteração funcional como, déficit de oxigênio (O2). O principal regulador da homeostase do O2 é o fator induzível por hipóxia-1α (HIF-1α) que na condição normóxia é sintetizado e degradado. No coração hipertrofiado, isquêmico, o HIF-1α torna-se estável e regula a transcrição de vários genes que aumentam a disponibilidade de O2. Além disso, aumenta a expressão das proteínas da via da glicose, com a finalidade de aumentar a oferta de energia. Embora, existam trabalhos que mostraram alteração do HIF-1 α, metabolismo de glicose e função cardíaca, não encontramos na literatura pesquisas que analisaram o comportamento e a associação do HIF-1α com o metabolismo glicídico, estrutura e função ventricular durante a evolução da remodelação por EAo. Objetivos gerais – Analisar durante o processo de evolução da RC o comportamento do HIF-1α, metabolismo da glicose, estrutura e função ventricular e a associação entre o HIF-1α e estas variáveis. Material e métodos – Foram utilizados dois grupos de ratos Wistar: controle operado (Sham, n=48) e EAo (n=48): os animais foram submetidos a cirurgia e no grupo EAo foi implantado um clipe de 0,60 mm de diâmetro na raiz da aorta. Os ratos foram avaliados no... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction - The experimental supravalvar aortic stenosis (AS) is used to induce pathological cardiac remodeling (CR); this model causes, initially, diastolic dysfunction and, later, systolic disorder and heart failure (HF). Different factors may contribute to these cardiac functional alterations, such as oxygen (O2) deficiency. The main regulator of O2 is hypoxia-inducible transcription factor (HIF-1α) that in normoxia condition is synthesized and degraded. In the hypertrophied, ischemic heart, HIF-1α becomes stable and regulates the transcription of several genes that increase O2 availability. In addition, it increases the expression of the glucose pathway proteins, in order to increase energy supply. Although there are studies that have shown alterations in HIF-1α, glucose metabolism and cardiac function, we have not found in the literature studies that investigated the behavior and association of HIF-1α with glucose metabolism, ventricular structure and function during the evolution of CR by AS.Objective - To analyze, during the course of CR evolution, the behavior of HIF-1α, glucose metabolism, ventricular structure and function, and the association between HIF-1α and these variables. Material and methods - Two groups of rats were studied: operated control (Sham, n=48) and supravalvar aortic stenosis (AS, n=48): the animals underwent surgery and in the AS group a clip of 0.60 mm diameter was placed at the aorta’s root. The rats were evaluated at 2, 6, 18 weeks after su... (Complete abstract click electronic access below) / Doutor

Submitted by PAULA GRIPPA SANT'ANA null (paulagrippa@yahoo.com.br) on 2018-03-28T13:33:43Z No. of bitstreams: 1 Tese Doutorado Paula Grippa Sant Ana.pdf: 2655001 bytes, checksum: d70cef401afff8d2daed0e55b5009291 (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-03-29T17:06:19Z (GMT) No. of bitstreams: 1 santana_pg_dr_bot.pdf: 2655001 bytes, checksum: d70cef401afff8d2daed0e55b5009291 (MD5) / Made available in DSpace on 2018-03-29T17:06:19Z (GMT). No. of bitstreams: 1 santana_pg_dr_bot.pdf: 2655001 bytes, checksum: d70cef401afff8d2daed0e55b5009291 (MD5) Previous issue date: 2018-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução - A estenose aórtica supravalvar (EAo) experimental é utilizada para induzir a remodelação cardíaca (RC) patológica; esse modelo provoca, inicialmente disfunção diastólica e, posteriormente, distúrbio sistólico e insuficiência cardíaca (IC). Diferentes fatores podem contribuir para essa alteração funcional como, déficit de oxigênio (O2). O principal regulador da homeostase do O2 é o fator induzível por hipóxia-1α (HIF-1α) que na condição normóxia é sintetizado e degradado. No coração hipertrofiado, isquêmico, o HIF-1α torna-se estável e regula a transcrição de vários genes que aumentam a disponibilidade de O2. Além disso, aumenta a expressão das proteínas da via da glicose, com a finalidade de aumentar a oferta de energia. Embora, existam trabalhos que mostraram alteração do HIF-1 α, metabolismo de glicose e função cardíaca, não encontramos na literatura pesquisas que analisaram o comportamento e a associação do HIF-1α com o metabolismo glicídico, estrutura e função ventricular durante a evolução da remodelação por EAo. Objetivos gerais – Analisar durante o processo de evolução da RC o comportamento do HIF-1α, metabolismo da glicose, estrutura e função ventricular e a associação entre o HIF-1α e estas variáveis. Material e métodos – Foram utilizados dois grupos de ratos Wistar: controle operado (Sham, n=48) e EAo (n=48): os animais foram submetidos a cirurgia e no grupo EAo foi implantado um clipe de 0,60 mm de diâmetro na raiz da aorta. Os ratos foram avaliados nos momentos de 2, 6, 18 semanas após cirurgia e na fase de IC grave. Os subgrupos Sham2, 6, 18, IC, e EAo2, 6, 18, IC foram constituídos por 12 animais. A estrutura e função cardíaca foram analisadas por ecocardiograma. A hipertrofia cardíaca foi também avaliada, post mortem. No miocárdico foram analisadas a expressão do HIF-1α, das proteínas da glicólise [hexoquinaseII (HKII), fosfofrutoquinase-2 (PFK-2)], via aeróbica [piruvato desidrogenase (PDH)], via anaeróbica [lactato desidrogenase (LDH)], da captação de glicose [transportador de glicose 1 e 4 (GLUT1 e GLUT4), do receptor de insulina (IR), do fosfatoinositol-3- quinase (PI3K) e quinase ativada pela adenosina monofosfato (AMPK)] pela técnica de Western Blot. As atividades das HK, PK, LDH, citrato sintase (CS) e a concentração de lactato foram analisadas por ensaio enzimático. Análise estatística foi realizada pela técnica de variância (ANOVA) para o esquema fatorial 2x4, complementada com teste de comparações múltiplas de Tukey (paramétrico) e Dunn (não paramétrico). Aassociação entre o HIF-1α e os conjuntos de variáveis foi estudada por meio da correlação canônica. Todas as conclusões estatísticas foram discutidas ao nível de 5% de significância. Resultados: Os principais achados significativos deste estudo foram: a) acentuação da hipertrofia ventricular esquerda durante a evolução da RC, alteração precoce na função diastólica e severa disfunção sistólica e diastólica na fase de IC grave; b) aumento do HIF-1α no início da RC e agravamento na fase de IC ; c) alteração precoce no metabolismo da glicose, com acentuação da via glicolítica e desvio para a via anaeróbica a partir da 6ª semana de EAo; d) associação significativa entre o HIF-1α e alteração estrutural, função diastólica e metabolismo da glicose. Conclusões: a) há aumento do HIF-1α e reprogramação do metabolismo da glicose, hipertrofia e disfunção diastólica a partir da 2ª semana de EAo; b) durante a evolução da RC ocorre elevação do HIF-1α, das proteínas da captação de glicose e via glicolítica com desvio para via anaeróbia; c) há associação canônica entre o conjunto do HIF-1α com o agrupamento das variáveis relacionadas com a via da glicose, estrutura e função diastólica cardíaca. / Introduction - The experimental supravalvar aortic stenosis (AS) is used to induce pathological cardiac remodeling (CR); this model causes, initially, diastolic dysfunction and, later, systolic disorder and heart failure (HF). Different factors may contribute to these cardiac functional alterations, such as oxygen (O2) deficiency. The main regulator of O2 is hypoxia-inducible transcription factor (HIF-1α) that in normoxia condition is synthesized and degraded. In the hypertrophied, ischemic heart, HIF-1α becomes stable and regulates the transcription of several genes that increase O2 availability. In addition, it increases the expression of the glucose pathway proteins, in order to increase energy supply. Although there are studies that have shown alterations in HIF-1α, glucose metabolism and cardiac function, we have not found in the literature studies that investigated the behavior and association of HIF-1α with glucose metabolism, ventricular structure and function during the evolution of CR by AS.Objective - To analyze, during the course of CR evolution, the behavior of HIF-1α, glucose metabolism, ventricular structure and function, and the association between HIF-1α and these variables. Material and methods - Two groups of rats were studied: operated control (Sham, n=48) and supravalvar aortic stenosis (AS, n=48): the animals underwent surgery and in the AS group a clip of 0.60 mm diameter was placed at the aorta’s root. The rats were evaluated at 2, 6, 18 weeks after surgery and at the severe HF phase. The subgroups Sham2, 6, 18, HF and AS2, 6, 18, HF were composed of 12 animals/group. Cardiac structure and function were analyzed by echocardiogram. Cardiac hypertrophy was also evaluated, post mortem. The expression of myocardial: HIF-1α; glycolytic proteins [hexokinase II (HKII), phosphofructokinase-2 (PFK-2), pyruvate dehydrogenase (PDH) and lactate dehydrogenase (LDH)]; glucose uptake proteins [intracellular glucose transporters (GLUT1 and GLUT4)]; insulin receptor (IR); phosphateinositol-3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) were analyzed by Western Blot. The activities of HKII, pyruvate kinase (PK), LDH and citrate synthase (CS) were also analyzed by enzymatic assays, and lactate concentration was also measured. Statistical analysis was performed by analysis of variance (ANOVA) technique for the 2x4 factorial scheme, complemented with Tukey's (parametric) or Dunn’s (non-parametric) multiple comparisons test. The association between HIF-1α and the sets of variables was analyzed through canonical correlation. All statistical conclusions were discussed at the 5% significance level. Results - The main significant findings of this study were: a) accentuation of left ventricular hypertrophy during the course of CR, early alteration in diastolic function and severe systolic and diastolic dysfunction in the phase of severe heart failure; b) increased HIF-1α at the onset of CR and worsening in severe HF phase; c) early changes in glucose metabolism, with enhancement of the glycolytic pathway and switch to the anaerobic pathway from the 6th week of AS; d) significant association between HIF-1α and cardiac structural alteration, diastolic function and glucose metabolism. Conclusions - a) there is an increase in HIF-1α, reprogramming of glucose metabolism, hypertrophy and diastolic dysfunction from the 2 nd week of AS; b) during the evolution of CR, there is an elevation in HIF-1α, in glucose uptake and glycolytic pathway proteins with switch to the anaerobic pathway; c) there is an association between HIF-1α and the grouping of variables related to the glucose pathway, cardiac structure and diastolic function. / CNPQ 442822/2014-6

No description available.

Le rétrécissement aortique calcifie (RAC) est la valvulopathie la plus fréquente dans les pays occidentaux et touche environ 2% des sujets de plus de 65 ans. Initialement considérée comme une dégénérescence passive de la valve aortique liée à l’âge, le RAC est actuellement considéré comme une pathologie complexe et hautement régulée et qui aboutit à un épaississement et à une calcification des feuillets valvulaires aortiques. A ce jour les mécanismes initiateurs et favorisant la progression du RAC ne sont pas complètement élucidés, et d’autre part, aucun traitement ne s’est avéré efficace pour ralentir ou stopper son évolution. Le remplacement valvulaire aortique (chirurgical ou percutané) reste le seul traitement en cas de rétrécissement aortique serré. D’autre part, il n’existe aucun modèle animal fiable et reproductible du RAC permettant de mieux comprendre la physiopathologie de cette valvulopathie et de tester de nouvelles cibles thérapeutiques. Dans le laboratoire, nous avons fait l’hypothèse que la dysfonction de l’endothélium valvulaire jouait un rôle important dans l’initiation et la progression du RAC, et nous souhaitons utiliser un modèle animal permettant d’évaluer l’effet de nouvelles thérapeutiques. Ce travail porte donc sur l’évaluation du rôle du système endothélinergique dans la sténose aortique calcifiée et le développement d’un nouveau modèle animal murin de RAC. Dans notre première étude, nous nous sommes intéressés au modèle de souris EgfrWa2/Wa2. Ce modèle est induit par la substitution du résidu amine glycine par une valine. Les souris EgfrWa2/Wa2 homozygotes pour la mutation voient leur activité tyrosine kinase diminuée de 90%. Ce modèle induit un épaississement fibreux des feuillets valvulaires avec peu de calcifications. Cependant, l’augmentation du flux transaortique n’est pas liée a un RAC mais a une insuffisance aortique (IA). Nous avons évalué dans ce modèle l’effet d’un régime enrichi en graisse et d’une supplémentation en vitamine D3. Malgré une augmentation des taux sériquesdu cholestérol, de la vitamine D3 et de la calcémie, nous n’avons pas observé d’augmentation de la calcification. Le modèle EgfrWa2/Wa2 reste essentiellement un modèle d’IA avec le développement d’un RAC qui reste rare ou absent. Dans notre seconde étude, nous avons évalué le rôle du système endothélinergique dans des cultures primaires de cellules valvulaires interstitielles (hVICs) et endothéliales (hVECs) humaines, prélevées lors d’un remplacement valvulaire aortique chirurgical chez des patients ayant un RAC serré. Les valves de patients traités par une intervention de Bentall ont été utilisées comme groupe contrôle. Nous avons tout d’abord observé, par RT-PCR quantitative, que les hVECs issues de valves sténosées présentaient une augmentation non significative de l’ARNm codant pour l’endothéline et une augmentation significative de l’ARNm codant pour le récepteur ET-B, ainsi qu’une diminution significative de l’enzyme de conversion de l’endothéline dans les hVECs par rapport aux hVECs issues de valves contrôles. Le récepteur ET-B était également surexprimé dans les hVICs par rapport aux valves contrôles. En revanche, nous n’avons pas retrouvé de variation d’expression du récepteur ET-A dans les hVICs. Nous avons ensuite évalué l’effet de l’endotheline-1 (ET-1) dans les hVICs. Nous avons retrouvé que les hVICs calcifient lorsqu’elles sont en présence d’ET-1. Ces données suggèrent une implication du système endothélinergique dans la calcification valvulaire aortique. Des études complémentaires sont nécessaires pour mieux comprendre son implication, notamment en évaluant l’effet d’antagoniste des récepteurs de l’endothéline dans des cultures de hVICs puis dans un modèle animal fiable mimant cette pathologie. / Aortic stenosis (AS) is the most common valvulopathy in Western countries and affects approximately 2% of subjects over 65 years of age. Originally considered a passive age-related degeneration of the aortic valve, AS is currently considered a complex and highly regulated pathology that results in thickening and calcification of aortic valve leaflets. To date the mechanisms initiating and promoting the progression of AS are not completely understood and secondly, no treatment has been effective to slow or stop its evolution. Aortic valve replacement (surgical or percutaneous) remains the only treatment for severe aortic stenosis. On the other hand, there is no reliable and reproducible animal model of AS to better understand the pathophysiology of this valvulopathy and to test new therapeutic targets. In the laboratory, we hypothesized that valvular endothelial dysfunction plays an important role in the initiation and progression of AS and we wish to use an animal model to evaluate the effect of new therapeutics. This work focuses on assessing the role of the endothelinergic system in AS and the development of a novel mouse animal model of AS. First, we used the EgfrWa2/Wa2 mouse model. This model is induced by the substitution of the amino glycine residue by a valine. The EgfrWa2/Wa2 mice homozygous for the mutation have their tyrosine kinase activity decreased by 90%. This model induces fibrous thickening of the leaflets with little calcification, but the increase in transaortic flow is not related to AS but to aortic regurgitation (AR). In this model we evaluated the effect of a fat-enriched diet and vitamin D3 supplementation. Despite increased serum levels of cholesterol, vitamin D3 and serum calcium, we did not observe an increase in calcification. The EgfrWa2/Wa2 model remains essentially a model of AR whereas AS remains rare or absent. Second, we evaluated the role of the endothelinergic system in primary cultures of human interstitial valvular (hVICs) and endothelial (hVECs) cells, obtained from AS patients treated by surgical aortic valve replacement. The valves of patients treated by a Bentall procedure were used as a control group. We first observed, by quantitative RT-PCR, that stenotic valves showed an increase in mRNA encoding endothelin and for its ET-B receptor and a decrease in the endothelin converting enzyme in the hVECs compared to the control valves. The ET-B receptor was also overexpressed in the hVICs compared to the control valves. We did not find any variation in expression of its ET-A receptor in hVICs. We then assessed the effect of endothelin-1 (ET-1) in the hVICs. We found that hVICs calcify when they are in the presence of ET-1. These data suggest involvement of the endothelinergic system in aortic valve calcification. Further studies are needed to better understand its involvement, notably by evaluating the effect of endothelin receptor antagonist in hVICs cultures and then in a reliable animal model mimicking this pathology

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