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Law, Jonathan Philip 
ORCID: https://orcid.org/0000-0002-4900-9618
(2023).
Investigating the role of fibroblast growth factor 23 in the pathogenesis of uraemic cardiomyopathy.
University of Birmingham.
Ph.D.
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Law2023PhD.pdf
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Abstract
Uraemic cardiomyopathy, or CKD-associated cardiomyopathy, describes the clinical syndrome of myocardial hypertrophy and fibrosis, systolic and diastolic left ventricular failure found in chronic kidney disease, resulting in increased cardiovascular mortality attributable to heart failure and sudden cardiac death from cardiac arrhythmia. Circulating hormone fibroblast growth factor 23 (FGF23) is significantly elevated in chronic kidney disease and has previously been associated with cardiac remodelling and mechanoelectrical dysfunction. The work described in this thesis examines the hypothesis that FGF23 is a major player in the pathogenesis of uraemic cardiomyopathy by activating cardiac fibroblasts and is disrupting cardiac ionic handling.
In this study, chronic activation of human cardiac fibroblasts led to an irreversible myofibroblast phenotype. FGF23 did not cause activation of human cardiac fibroblasts in vitro. Acute FGF23 treatment of ex vivo perfused murine hearts demonstrated shortening of left ventricular action potential and calcium transient duration by optical mapping, and increased incidence of cardiac arrhythmias. Moderate levels of FGF23 elevation in young adult mice caused arrhythmias without affecting cardiac ventricular morphology or mechanical function. These findings suggest that FGF23 causes increased cardiac arrhythmic phenomena through impaired cardiac ionic handling, which precedes clinically detectable hypertrophy and fibrosis.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Cardiovascular Sciences | |||||||||
| Funders: | British Heart Foundation | |||||||||
| Subjects: | R Medicine > R Medicine (General) R Medicine > RC Internal medicine |
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| URI: | http://etheses.bham.ac.uk/id/eprint/14227 |
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