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HSF1 Activators Lower cardiomyocyte damage: towards a novel Therapeutic approach to REVERSE Atrial Fibrillation

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Title:  HSF1 Activators Lower cardiomyocyte damage: towards a novel Therapeutic approach to REVERSE Atrial Fibrillation. HALT&REVERSE
Investigators:   PhD student UMCG (vacancy), PhD student EMC (vacancy)
Promoter:  RH Henning
Co-promoters:  BJJM Brundel and N de Groot (EMC)
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. Treatment of AF is difficult, which is rooted in the persistent and progressive nature of the disease. AF persistence is caused by progressive damage in cardiomyocytes, which make the atria more vulnerable for the arrhythmia. In particular structural remodeling is sustainable and impairs electrical coupling and the functional recovery to sinus rhythm by pharmacological and electrical cardioversion. It should be noted that structural remodeling is already present when AF is diagnosed. Currently, no effective therapy resolving the structural remodeling is known, as present medication targets reversible electrical changes and therefore has limited impact on patient outcome. Thus, reversal of structural remodeling represents a key target to accomplish and maintain cardiac sinus rhythm after AF conversion. Previously, we showed that exhaustion of the cardio-protective heat shock proteins (HSPs), and especially HSP27, importantly contributes to structural remodeling in patients with AF. In addition, high HSP27 levels in blood predict sinus rhythm maintenance after catheter ablation in patients with paroxysmal AF. Also, boosting of HSPs, by the heat shock factor-1 (HSF1) activator GGA, resulted in attenuation of AF initiation and progression in various experimental models for AF. This finding is further exploited by a bio-pharmaceutical company Nyken BV, which designed and identified small molecules with improved HSF1 activating and pharmaco-chemical properties compared to GGA. These compounds boost HSP expression, including HSP27, and reveal cardioprotective effects. Together, the findings uncover HSPs to halt structural remodeling and AF initiation and progression. However, it is still unclear whether induction of HSPs also improve the success rate of cardioversion by reversion of the cardiomyocyte structure and function. In this research program we intend to explore whether boosting of HSPs by genetic approaches and by treatment with experimental drugs (new chemical entities) reverses cardiomyocyte structure and function and thereby halt AF initiation and progression. To this end, both experimental models of AF and patient material will be investigated. 
Financing: LSH-NWO, Dutch Heart Foundation (2x PhD student, technician)
Start: 01-04-2014
End: 01-04-2018

Projects
Organ damage and the role of CBS in hibernation.
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The CBS/H2S pathway in the brain.
Platelet dynamics in natural and pharmacologically induced hibernation.
Liver fibrosis and hibernation.
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Limiting the impact of stroke.
Identification of kinomic key proteins involved in tachycardia and stretch induced cardiomyocyte remodeling.
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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Role of cyclooxygenase signalling on vascular dysfunction in the metabolic syndrome.
Vascular (Dys-)Function as a Determinant of Susceptibility to Diabetic Nephropathy: a Focus on Myogenic Constriction.