BACKGROUND Aortic stenosis affects not only the valve but also the myocardium. In response to the increased afterload, left ventricular hypertrophy initially occurs as a compensatory response to maintain wall stress and cardiac output but ultimately, decompensation and heart failure ensues. The transition from adaptation to decompensation is driven by myocyte death and myocardial fibrosis. The aims of the thesis are to investigate cardiovascular magnetic resonance assessment of disease severity and myocardial fibrosis, and explore its relationship with other biomarkers of disease activity and clinical outcome in patients with aortic stenosis. METHODS AND RESULTS The conventional assessment of aortic stenosis relies heavily on two-dimensional and Doppler echocardiography but there are inherent limitations in echocardiography that can affect the severity classification. I demonstrated that cardiovascular magnetic resonance offered a more accurate estimation of left ventricular volumes and mass, and excellent myocardial characterization. Indeed, inaccurate stroke volume estimation by Doppler echocardiography and inconsistent thresholds in current guidelines accounted for more than 40% of patients with discordant small-area, lowgradient aortic stenosis. These data may explain the variable prognosis reported in this unique group of patients, and argue for more accurate assessment of borderline cases with cardiovascular magnetic resonance. Late gadolinium enhancement imaging detects focal areas of established myocardial fibrosis. In many conditions, including aortic stenosis, a more diffuse form of fibrosis predominates, which is potentially reversible and not readily identified by late gadolinium enhancement. Recently several myocardial T1 mapping approaches have been developed to quantify diffuse fibrosis. Using a standardized and systematic approach, I compared several commonly used T1 mapping techniques and identified that extracellular volume had the best profile (reproducibility and discriminatory potential) for the identification of diffuse fibrosis in patients with aortic stenosis. Cardiac troponin is a structural protein present in the cardiac myocytes. Recent advances in assay technology have substantially improved sensitivity, allowing quantification of troponin concentrations with a high degree of precision in everyone. In more than 250 patients with aortic stenosis, I demonstrated that cardiac troponin I concentrations were independently associated with markers of left ventricular decompensation (hypertrophy and fibrosis) and predicted clinical outcome in patients with aortic stenosis. This suggests that myocardial fibrosis detected by cardiovascular magnetic resonance is consequent on myocardial injury secondary to left ventricular decompensation. Left ventricular hypertrophy with strain pattern on a 12-lead electrocardiogram is associated with poor outcome in patients with aortic stenosis, but the mechanism of this electrocardiographic pattern has not been described. In more than 300 patients with aortic stenosis, I demonstrated that these characteristic repolarization abnormalities were a highly specific marker of focal mid-wall myocardial fibrosis (specificity of 99% and sensitivity of 54%). Moreover, the prognostic value of this electrocardiographic pattern was again confirmed with markedly worse long-term outcomes in these patients. CONCLUSION I have demonstrated that cardiovascular magnetic resonance can assist in the assessment of disease severity in patients with aortic stenosis and discordant echocardiographic findings. Moreover, I have validated the assessment of diffuse myocardial fibrosis, as well as, demonstrated the close association between myocardial fibrosis and biomarkers of myocardial injury and electrocardiographic strain pattern that predicted an adverse outcome in patients with aortic stenosis.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Hana Pešková Supervisor: PharmDr. Marie Vopršalová, CSc. Title of diploma thesis: Effects of some flavonoids in isolated rat aortic rings Flavonoids with their wide range of effects are known for having positive influence on human health. It mainly concerns significant antioxidant and anti- inflammatory characteristics and cardiovascular diseases incidence reducing effects. The aim of this study was examination of vasorelaxant effects of selected flavonoids from isoflavonoid group: formononetin, isoformononetin, prunetin and ononin, occuring especially in Fabaceae family. The vasorelaxation potential of tested substances was examinated in in vitro conditions on isolated aortic rings of rat. The effect of increasing doses of individual flavonoids on preparation, with intact endothelium after previous precontraction with norepinefrine, was monitored (10-5 M). From measured values, there were DRC curves, EC50 values created and an evaluation was made. According to analysis of the results, the most significat activity has fromononetin (EC50 2,081 . 10-5 M) and isoformononetin (EC50 2,081, 10-5 M). Ononin showed almost no vasodilatory effect.

Endovascular aortic aneurysm repair (EVAR) is the procedure of choice in most patients with abdominal aortic aneurysm. The drawbacks of EVAR are a higher rate of complications and frequent need for reinterventions, requiring regular postoperative follow-up. Non-stratified follow-up may have a deleterious effect on patients and the health care system. The aim of this thesis is to develop strategies that can stratify the EVAR follow-up programme according to an individual patient´s risk profile. Study I, an international multicentre study of all abdominal aortic aneurysm (AAA) patients with EVAR in three centres (2000 to 2011) demonstrated a lower rate of late complications and reinterventions in patients with sac shrinkage during the first postoperative year, compared to the non-shrinkage group. Study II, an international multicentre study of patients treated for a ruptured aortic aneurysm with EVAR in three centres (2000 to 2012) demonstrated that ruptured EVAR (rEVAR) in patients with hostile anatomy is associated with a high rate of graft-related complications, reinterventions and increased overall mortality. Study III, a two-centre cohort study of 326 patients with EVAR (2001 to 2012), with first postoperative computerised tomographic angiography (CTA) within one year of the operation. Patients with adequate proximal and distal sealing zones and no endoleak in the first postoperative CTA had significantly lower risk for AAA-related complications and reinterventions up to five years postoperatively. Study IV, studied all complications and reinterventions in a two-centre cohort study of all EVAR patients (1998 to 2012), One-fourth of the patients in the study developed complications during a mean follow-up of five years. Most complications were asymptomatic imaging-detected. Ultrasound could detect most of the clinically significant complications.

Among the four valves of the heart, the aortic valve (AV) is frequently affected by disease. When progressive dilatation of the valve produces a leak when the valve should close (regurgitation), repair may be possible. AV repair is a desirable option because, contrary to AV replace-ment using a prosthesis, it does not require life-long anticoagulation treatment, and retains the original tissues that naturally combat structural degradation. All the AV repair procedures developed by cardiac surgeons require a good stabilization of the ventriculo-aortic junction (VAJ) diameter, through annuloplasty or reimplantation, for long-term success. In the present work, a preliminary design for a new type of annuloplasty ring is proposed that surgeons could tailor to the each valve’s shape and suture inside the VAJ. The design consists in wrapping a commonly available surgical biomaterial into a ring of controlled radial flexibility. For sizing and material selection, several models of increasing complexity were created to account for the anisotropic, hyperelastic nature of all the materials involved. First, an analytical model was programmed in MATLAB to assess the radial flexibility of annuloplasty rings formed with different biomaterials and select those that could match the physiological VAJ radial flexibility between systolic and diastolic pressures. The same program was also used to reproduce the experimental radial and longitudinal stretches of the human VAJ from 0 to 140 mmHg pressures. The analytical models were used to calibrate the parameters of independent finite element (FE) models of the VAJ and ring. Finally, the FE approach was extended to simulate the ring after suturing inside the VAJ, to determine the radial flexibility of the assembly under pulsatile pressure. Supple Peri-Guard® bo-vine pericardium patches used in transverse orientation emerged as the best currently available material option for the proposed ring, although a material providing more physiological radial flexibility would be desirable.

L’anévrisme de l’aorte abdominale (AAA) représente un problème majeur de santé publique et est associé à des taux extrêmement élevés de mortalité en cas de rupture aortique. Il est classiquement associé à l’athérosclérose et aux facteurs de risque cardiovasculaires, à l’exception du diabète qui jouerait un rôle protecteur dans la maladie. Bien que certaines études aient montré une infiltration de macrophages et une modification de l’expression des micro-ARNs dans la paroi anévrismale, leurs rôles respectifs dans le développement de l’AAA ne sont pas encore totalement élucidés. Même si les modèles expérimentaux classiques sont utiles pour adresser cette question, ils ne miment pas parfaitement la physiopathologie humaine. Nous avons développé un nouveau modèle d’AAA associant application topique d’élastase et neutralisation systémique du TGFβ permettant de reproduire les principales caractéristiques de l’AAA humain et induisant une rupture aortique. Les objectifs de ce travail étaient de: -1/ Caractériser le phénotype des monocytes/ macrophages dans ce modèle murin d’AAA. -2/ D’étudier l’expression des micro-ARNs dans ce modèle. -3 / Les mécanismes impliqués dans la relation négative entre diabète et AAA étant à ce jour peu connus, le 3ème objectif était de mettre en place une étude clinique afin d’étudier l’expression des micro-ARNs chez des patients diabétiques ayant un AAA.L’application d’élastase associée à la neutralisation du TGFβ chez des souris C57/Bl6j entrainait une augmentation significative de la densité de macrophages infiltrés dans le tissu aortique anévrismal. L’analyse des tissus aortiques a montré des modifications significatives des marqueurs des macrophages pro-inflammatoires dits « M1 » et des marqueurs des macrophages impliqués dans la réparation tissulaire, dits « M2 ». Afin de mieux comprendre le rôle des macrophages dans ce modèle murin, des injections de clodronate ont été réalisées pour dépléter ces cellules. L’injection de clodronate diminuait de façon significative la dilatation anévrismale et prévenait la rupture. Ceci était associé à une préservation de la matrice extracellulaire et une modification de l’expression de certains marqueurs des macrophages, dont l’arginase-1 (ARG1), molécule impliquée dans la réparation tissulaire. La proportion de macrophages exprimant l’ARG1 augmentait en fonction de la sévérité de l’AAA. Enfin, la neutralisation du TGFβ induisait une diminution significative d’un type particulier de monocytes dits « Sat-Mono», impliqués dans la fibrose. Cette étude a ainsi montré le rôle des macrophages dans le développement et la rupture anévrismale avec une modification de leur phénotype. 752 micro-ARNs ont ensuite été analysés dans le tissu aortique, ce qui a permis d’identifier les micro-ARNs dont l’expression était modifiée dans ce modèle par rapport au groupe contrôle. Enfin, l’expression des micro-ARNs a été recherché chez l’homme en mettant en place une étude clinique. Bien que l’AAA chez l’homme soit classiquement associé à l’athérosclérose et aux facteurs de risque cardiovasculaire, il est paradoxalement négativement associé au diabète. Les mécanismes en cause sont encore peu connus. Nous avons comparé l’expression des micro-ARNs entre des patients diabétiques et non-diabétiques présentant un AAA. Cette étude pilote a permis d’identifier des cibles potentielles impliquées dans l’association négative entre diabète et AAA. / Abdominal aortic aneurysm (AAA) is a major public health concern and is associated with extremely high rates of mortality in case of aortic rupture. AAA is most often associated with atherosclerosis and cardiovascular risk factors, except diabetes that may rather play a protective role in the disease. Even though several studies have highlighted an infiltration of macrophages and changes of the expression of micro-RNAs in the aneurysmal wall, their role in AAA is still not fully understood. While experimental animal models are very useful to address this question, none of them perfectly mimics human pathophysiology. We recently created a new murine model of AAA based on topic application of elastase on the aorta associated with systemic TGFβ neutralization which reproduces the main human features of AAA and leads to fatal aortic rupture. The aims of this study were: -1/ Characterize the phenotype of monocytes/ macrophages in this murine model of AAA. -2/ Study the expression of micro-RNAs in this model. -3/ As the mechanisms involved in the negative association between diabetes and AAA are still poorly known, the third goal was to mount a clinical study to compare the expression of micro-RNAs between diabetic and non-diabetic patients with AAA. Topic application of elastase associated with systemic TGFβ neutralization in C57/Bl6j male mice led to a significant increase of macrophage infiltration in the aneurysmal tissue. This was associated with changes of the gene expression of the markers of the pro-inflammatory macrophages, called “M1” and of the macrophages involved in wound healing, called “M2”. To investigate the role of macrophages in this model, we used liposomes containing clodronate injections to deplete these cells. This led to significant decrease of the aortic dilatation and prevented rupture. This was associated with a better preservation of the extracellular matrix and significant changes in the gene expression of the markers of macrophages including arginase-1 (ARG1), a molecule involved in would healing. The proportion of macrophages expressing ARG1 increased with the severity of the AAA. At last, TGFβ neutralization led to a significant decrease of a population of macrophages involved in fibrosis, called “Sat-Mono”. This study highlighted the role and the phenotypic changes of macrophages during AAA development. We then analyzed the expression of 752 micro-RNAs in the aneurysmal aortic tissue which allowed identifying the micro-RNAs whose expression varied in the murine model. At last, the expression of micro-RNAs was investigated in patients with AAA. We compared the expression of micro-RNAs between diabetic and non-diabetic patients with AAA. This pilot study led to the identification of micro-RNAs that could potentially represent new targets involved in the negative association between diabetes and AAA.

There are well over 100,000 Americans on the kidney transplant list with a median wait time of 3.6 years. However, about 17 American die each day waiting for a kidney transplant, with vascular calcification being one of the most common causes [1, 2]. One vessel that is highly susceptible to vascular calcification is the aorta leading to negative cardiovascular outcomes that are secondary to kidney disease [3]. Therefore, understanding the effects that kidney disease has on disrupting the physiology of the vasculature, and finding potential therapeutic options, are imperative to those waiting for a life-saving kidney transplant. The present study aimed to test two hypotheses: (1) Aortic calcification leads to a decrease in stress in the thoracic and abdominal aorta of a young adult mouse. (2) The attenuated aortic stress seen in aortic calcification is due to the decreased expression of smooth muscle ⍺-actin (SM⍺-Actin). To test these hypotheses, calcification was induced in the ex vivo mouse aorta, followed by histological staining for calcium deposits, immunoblots for SM⍺-Actin, and measurements of aortic stress. The results of this study support the hypotheses in that calcification impairs aortic stress and it does so by decreasing the expression of SM⍺-Actin. The present study is the first to show the effect of phosphate-induced calcification on stress and expression of SM⍺-Actin in an ex vivo mouse aorta. This study is relevant to researchers as it shows key differences between studying vascular calcification in vitro compared to ex vivo. Therefore, investigating the mechanisms of aortic calcification using an ex vivo model, may be more applicable to human patients. / 2024-05-17T00:00:00Z

No description available.

Cardiovascular involvement is commonly reported in various muco- polysaccharidoses. We report a first case of Sanfilippo syndrome type A in a 12-year-old white female who has developed combined progressive mitral valvar regurgitation due to prolapse and aortic regurgitation.

Objectives To compare incidence of aortic regurgitation (AR), paravalvular AR and valvular performance with Doppler hemodynamic parameters following transcatheter aortic valve replacement (TAVR) with Edwards valve (EV) versus CoreValve (CV). Currently, there are scarce data on post-TAVR echocardiographic outcomes comparing EV and CV. Methods PubMed and the Cochrane Center Register of Controlled Trials were searched through May 2015. Twenty studies (n = 11,244) comparing TAVR procedure that used EV (n = 6445) and CV (n = 4799) were included. End points were post-TAVR moderate to severe AR and paravalvular AR, effective orifice area (EOA), mean trans-aortic pressure gradient (MPG), peak trans-aortic pressure gradient (PPG) and left ventricular ejection fraction (LVEF). The mean difference (MD) or relative risk (RR) with 95% confidence interval (CI) was computed and p < 0.05 was considered as a level of significance. Results Moderate to severe AR and paravalvular AR were significantly lower in EV group (RR: 0.57, CI: 0.52–0.63, p < 0.00001 and RR: 0.40, CI: 0.25–0.63, p < 0.0001 respectively) compared to CV group. EOA and PPG were not significantly different between EV and CV groups. MPG was significantly lower among patients in CV group (MD: 1.08, CI: 0.05–2.10, p = 0.04). LVEF was significantly higher in patients in EV group (MD: 2.26, CI: 0.77–3.74, p = 0.03). Conclusions This study showed CV is associated with higher incidence of post-TAVR moderate to severe paravalvular AR. Echocardiographic valvular performance measures (MPG, LVEF) showed minimal but significant difference, which may not be clinically significant.

Objective: Aortic stenosis (AS) patients with eccentric hypertrophy (Ecc-LVH) have increased left ventricular (LV) size and possibly reduced ejection fraction (EF). However, previous studies suggest worse outcomes with concentric remodeling and hypertrophy. We hypothesized that Ecc-LVH pattern in AS patients will also be associated with greater heart failure (HF) and all-cause mortality (ACM). Methods: We queried the electronic medical record from a community-based university practice for all AS patients. We included patients with >60 days follow-up and interpretable Doppler echocardiograms. We recorded demographics, Doppler-echo parameters, laboratories, HF readmission and ACM with follow-up to 2083 days. There were 329 patients divided into 4 groups based on the presence of LV hypertrophy (LVH) and relative wall thickness (RWT) by echocardiography. Ecc-LVH had RWT<0.43 and LVH. Results: Patients with severe AS were older, had greater coronary disease prevalence, lower hemoglobin, greater LV mass index, more abnormal diastolic function, greater HF and ACM. Multivariate Cox proportional analysis revealed that valvulo-arterial impedance (p=0.017) and Ecc-LVH (p=0.033) were HF predictors. Brain natriuretic peptide>100 pg/ml (p<0.001) and Ecc-LVH (p=0.019) were ACM predictors. ACM was increased in Ecc-LVH patients with both moderate (HR=3.67-8.18 vs other geometries, p=0.007-0.0007) and severe AS (HR=3.94-9.48 vs normal and concentric remodeling, p=0.0002). In patients with HF, Ecc-LVH was associated with greater HF in moderate AS vs normal geometry (HR=3.28, p=0.0135) and concentric remodeling (HR=2.66, p=0.0472). Conclusions: Patients with AS and Ecc-LVH have greater ACM than other LV geometries with both moderate and severe AS and greater HF in moderate AS.