Pathophysiological understanding of acute decompensated heart failure: a proteomic approach
[eng] INTRODUCTION: Heart failure is a dynamic pathological condition that frequently presents episodes of acute worsening, recognised as acute decompensated heart failure (ADHF). This is a complex clinical condition that may affect different organs and involve several pathophysiological mechanisms...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/208445 |
| Acceso en línea: | https://hdl.handle.net/2445/208445 http://hdl.handle.net/10803/690253 |
| Access Level: | acceso abierto |
| Palabra clave: | Cardiologia Proteïnes Espectrometria de masses Cardiology Proteins Mass spectrometry |
| Sumario: | [eng] INTRODUCTION: Heart failure is a dynamic pathological condition that frequently presents episodes of acute worsening, recognised as acute decompensated heart failure (ADHF). This is a complex clinical condition that may affect different organs and involve several pathophysiological mechanisms that remain incompletely understood. ADHF is often related to kidney dysfunction, which impacts disease evolution resulting in higher risk for adverse outcomes. It is our hypothesis that identification and better characterisation by proteomic approaches of proteins associated with heart failure decompensation would contribute to gain understanding of the disease pathophysiology, support a more accurate disease phenotyping, and better identify patients with poor disease evolution. OBJECTIVES: The aim of this thesis was to identify and characterise the differential protein signature in urine of ADHF patients in association with molecular functions and biological processes related to disease progression. METHODS: ADHF patients admitted to the emergency room at Hospital de la Santa Creu i Sant Pau were included in the study. Urine samples were analysed by an untargeted mass spectrometry approach and compared with a group of healthy subjects by 2 dimensional electrophoresis coupled to mass spectrometry (MALDI-ToF/ToF). In silico analysis was performed and proteins selected for further validation studies using specific immunoassays (ELISA), in urine and plasma/serum samples. ADHF comparison groups were defined by the glomerular filtration rate and left ventricular ejection fraction (LVEF). Healthy subjects were used to determine the normal range. Protein power to discriminate ADHF patients according to their pathology, disease severity, and prognosis was achieved by Receiver operating curve (ROC) and Kaplan-Meier survival curve analysis. Cell function mechanistic studies were also performed. RESULTS: A differential signature of 26 proteins (more than 1.5 fold), mostly of hepatic origin, was identified. These proteins relate to molecular functions and processes, such as transport, haemostasis, and immunity. Of note, we observed elevated levels in urine at hospital admission of transthyretin (TTR), antithrombin III (AT3), complement C3 (C3) and vitamin D binding protein (VDBP) when compared to HS. The increased urinary loss of proteins, such as TTR and retinol binding protein 4 (RBP4) may have a harmful impact on disease evolution resulting in higher risk for adverse outcomes after hospital discharge. Furthermore, high AT3 levels in urine and plasma identified those ADHF patients with renal dysfunction and preserved and mildly reduced LVEF. AT3, beyond its role in coagulation, correlates with C3, a key component of innate immunity, independently of systemic inflammation. Interestingly, C3 is localised in vascular extracellular matrix and stimulates cell functions such as adhesion, migration and cytoskeletal reorganisation. Levels of VDBP, along with cystatin C and KIM-1, could help to stratify ADHF patients at higher risk of developing kidney injury during hospitalisation. IN CONCLUSION, the results of this thesis show a urinary protein signature in ADHF patients highly diverse yet different from healthy individuals. The obtained results suggested a harmful impact of the differential protein signature on disease evolution resulting in a higher risk for adverse outcomes after hospital discharge. Future studies in larger populations are needed to validate the relevance of the identified differential protein signature in ADHF pathophysiology. |
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