Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Ευάγγελος Τέρπος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ιγνάτιος Οικονομίδης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευστάθιος Καστρίτης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κίμων Σταματελόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Γαβριατοπούλου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αλέξανδρος Μπριασούλης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Γεωργιόπουλος, Επίκουρος Καθηγητής, Τμήμα Ιατρικής, Πανεπιστήμιο Πατρών
Original Title:
Ο ρόλος της αναστολής του πρωτεασώματος στη μηχανική του μυοκαρδίου σε ανθρώπους
Translated title:
The role of proteasome inhibition in myocardial mechanics in humans
Summary:
Background: Ubiquitin-Proteasome System (UPS) is crucial for the normal function of the myocardial cells. In experimental settings, the inhibition of UPS has been found to affect the myocardial cell’s function, but the exact clinical role of UPS inhibition on the cardiac function has not been elucidated.
Aim and methods: The aim of this thesis was to gain insight into myocardial mechanics in humans following proteasome inhibition. Consequently, we prospectively included 48 patients with multiple myeloma and an indication to receive carfilzomib, which is an irreversible proteasome inhibitor. All patients underwent an initial evaluation and echocardiographic study with speckle tracking analysis to assess myocardial deformation. Carfilzomib was administered according to Kd treatment protocol. Patients underwent follow-up echocardiography at the 3rd and 6th month after carfilzomib initiation. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells at the aforementioned timepoints. Also, inflammation and cardiac injury biomarkers were measured at the timepoints, alongside with pulse wave velocity, flow-mediated dilation and blood pressure parameters. Another cohort of patients with multiple myeloma who were not treated with carfilzomib was used as a cardiotoxicity control group.
Results: We observed that at 3 months after treatment there was an early deterioration of the left ventricular (LV) segmental strain and deterioration of left atrial (LA) structure and function, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, we additionally observed global LV and right ventricular function depression (p<0.05 for all). The changes of these cardiac mechanics indices were independent of blood pressure, endothelial function, inflammation and cardiac injury levels. Further, changes in GLS, segmental LV strain and LA indices were associated with changes in PrA (p<0.05 for all). Finally, we observed that patients with baseline GLS<-18% or LA strain rate>1.71 were associated with null hypertension events.
Conclusion: Inhibition of the UPS system in a clinical setting induced a global cardiac deterioration.
Main subject category:
Health Sciences
Keywords:
Carfilzomib, Myocardial mechanics, Proteasome activity, Cardiotoxicity, Hypertension
Number of references:
199
