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REVersal of cardiomyocyte structural remodeling and Improvement of functional recoVEry in Atrial Fibrillation: REVIVE

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Title:  REVersal of cardiomyocyte structural remodeling and Improvement of functional recoVEry in Atrial Fibrillation: REVIVE
Investigators: D Zhang (post-doc), PhD student (vacancy)
Promoter: RH Henning
Co-promoter:  BJJM Brundel (PI: Established Investigator grant)
 Summary:  Atrial Fibrillation (AF) is the most common age-related cardiac arrhythmia accounting for about one-third of hospitalizations for arrhythmia with an annual cost of 13 billion euro in the European Union. Moreover, AF is associated with an increase in morbidity and mortality. Treatment of AF is difficult, which is rooted in the persistent nature of the disease.

AF persistence is caused by progressive changes in cardiomyocytes, which make the atria more vulnerable for the arrhythmia (‘AF begets AF’). As current medication targets reversible electrical changes, therapy has limited effect on patient outcome. The reversal of structural remodeling represents a key target to accomplish to maintain normal cardiac sinus rhythm after AF conversion. It is the aim of this project to uncover mechanisms that enhance structural restoration and revival of cardiomyocyte function in AF.

Opening up such exciting new avenues in AF research is enabled by our recently developed experimental AF models i.e. the tachypaced atrial cardiomyocyte and Drosophila model. With these models we identified the derailment of healthy protein homeostasis as the key element driving the structural remodeling and AF persistence. Derailment is caused by persistent activation of protein degradation, a blockade of protein translation and posttranslational changes in structural proteins causing microtubule disruption. In addition, exhaustion of the cardio-protective heat shock proteins, HSPB1 and HSPA5, contributes importantly. Likely, these factors also limit revival of the cardiomyocyte structure and function. Thus, we hypothesize that normalization of protein homeostasis reverses structural remodeling and represents an effective therapeutic approach to ‘revive’ cardiomyocyte function in AF.

Atrial cardiomyocytes, the Drosophila model and human atrial tissue of AF patients is used to 1) investigate which key modulator(s) of proteostasis obstruct reversal of structural remodeling, 2) identify additional key modulator(s) of reversibility, and 3) unravel mechanism how HSPs accelerate reversal of structural remodeling. We aim to disclose novel mechanisms that drive revival of cardiomyocyte function and identify drugable targets to enhance functional recovery after AF.

Financing: Dutch Heart Foundation, post-doc, PhD student, technician
Start: 01-04-2014
End: 01-04-2019

      

Projects
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Role of epigenetic regulation by histone acetylation in the induction of Atrial Fibrillation.
Reversal of cardiomyocyte remodeling in Atrial Fibrillation; the role of protein degradation and translation modulators.
REVersal of cardiomyocyte structural remodeling and Improvement of functional recoVEry in Atrial Fibrillation: REVIVE.
HSF1 Activators Lower cardiomyocyte damage: towards a novel Therapeutic approach to REVERSE Atrial Fibrillation. HALT&REVERSE
Mutations in HSPB5, HSPB7 and BAG3 lead to juvenile DCM.
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Vascular (Dys-)Function as a Determinant of Susceptibility to Diabetic Nephropathy: a Focus on Myogenic Constriction.