Interrogating human disease by transcriptomic and proteomic profiling in a sheep model for atrial fibrillation
Title (trans.)
Interrogando la enfermedad humana mediante transcriptomica y proteomica en un modelo de oveja de Fibrilación AuricularAuthor
Alvarez Franco, AlbaAdvisor
Manzanares Fourcade, MiguelEntity
UAM. Departamento de BioquímicaDate
2021-11-25Subjects
Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 25-11-2021Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization
and adverse cardiovascular events. AF is a complex disease with multiple risk factors and associated
comorbidities [74, 126] and remarkably, among them, AF is associated with a 5-fold risk of
stroke [100]. The global incidence is expected to double the current rates by 2050, and as the global
population increases its longevity, understanding the consequences of AF on an aged population
becomes more critical. Although AF has been under extensive research for more than 50 years,
there is a clear demand for more inclusive and large-scale approaches to understand the molecular
drivers responsible for AF, as well as the fundamental mechanisms governing the transition from
paroxysmal to persistent and permanent forms. In this doctoral thesis project, we have taken advantage
of a well-established model of tachypacing-induced long-standing AF in the sheep to analyse
in vivo the molecular changes that occur in the atria and systemically during the progression of AF
from paroxysmal to its long-lasting forms, always in comparison with paired surgically operated
sinus rhythm controls. We have performed transcriptomic and proteomic profiling of atrial tissue
and cardiomyocytes aswell as profiling the blood proteome. For the analysis of data, we have developed
our own pipelines, benchmarked different tools and carried out correlation-based integration
analysis and hierarchical modelling of longitudinal data in a Bayesian framework. We demonstrate
that the hallmarks of AF-induced atrial remodelling change only at early transitional stages at the
molecular level, but remain unaltered at later stages of the disease and that the left atrium undergoes
significantly more profound changes in its expression programme than the right atrium. By dissecting
the short time window between the paroxysmal and persistent forms, we proved that electrical
remodelling occurring in the left atria is sufficient to trigger molecular changes in less than a few
hours and we have confirmed that the pro-thrombotic state, inflammation, and lipid metabolism
are activated systemically as the result of AF per se, beyond being these processes associated with
pre-existing comorbidities. This pattern of dynamic changes in gene and protein expression replicate
the electrical and structural remodelling previously shown in animal models and in humans,
and uncover novel mechanisms potentially relevant for disease treatment
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