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The future of atrial fibrillation therapy: intervention on heat shock proteins influencing electropathology is the next in line.

Lanters EA, van Marion DM, Steen H, de Groot NM, Brundel BJ - Neth Heart J (2015)

Bottom Line: Currently, no effective therapy is known that can resolve this damage.Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients.Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF.This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF.

View Article: PubMed Central - PubMed

Affiliation: Unit Translational Electrophysiology, Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia accounting for one-third of hospitalisations. Treatment of AF is difficult, which is rooted in the progressive nature of electrical and structural remodelling, called electropathology, which makes the atria more vulnerable for AF. Importantly, structural damage of the myocardium is already present when AF is diagnosed for the first time. Currently, no effective therapy is known that can resolve this damage.Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients. Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF. However, it is still unclear whether induction of HSPs also prolongs the arrhythmia-free interval after, for example, cardioversion of AF.In this review, we discuss the role of HSPs in the pathophysiology of AF and give an outline of the HALT&REVERSE project, initiated by the HALT&REVERSE Consortium and the AF Innovation Platform. This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF.

No MeSH data available.


Related in: MedlinePlus

Geranylgeranylacetone (GGA) derivatives induce HSP70 expression and reveal cardioprotective effects. a Western blot showing induction of HSP70 levels in HL-1 cardiomyocytes treated with GGA and some of the GGA derivatives (Nyk compounds). b Representative calcium transient tracers of non-treated and normally paced (1 Hz) HL-1 cardiomyocytes (Control) or tachypaced cardiomyocytes (TP, 5 Hz) without or with treatment of 10 µM GGA or GGA derivatives (Nyk compounds) as indicated. c Overview of the central concept of HALT&REVERSE. Atrial fibrillation (AF) naturally progresses in time (red line), which is rooted in the underlying electropathology. By pharmacological induction of HSP levels (blue arrow), we aim to halt or even reverse electropathology and consequently AF progression (green line)
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Fig4: Geranylgeranylacetone (GGA) derivatives induce HSP70 expression and reveal cardioprotective effects. a Western blot showing induction of HSP70 levels in HL-1 cardiomyocytes treated with GGA and some of the GGA derivatives (Nyk compounds). b Representative calcium transient tracers of non-treated and normally paced (1 Hz) HL-1 cardiomyocytes (Control) or tachypaced cardiomyocytes (TP, 5 Hz) without or with treatment of 10 µM GGA or GGA derivatives (Nyk compounds) as indicated. c Overview of the central concept of HALT&REVERSE. Atrial fibrillation (AF) naturally progresses in time (red line), which is rooted in the underlying electropathology. By pharmacological induction of HSP levels (blue arrow), we aim to halt or even reverse electropathology and consequently AF progression (green line)

Mentions: Although protective effects with GGA were observed, an important disadvantage of GGA is its high LogP value, which is around 9, and therefore generally high dosages are required, as found in the dog studies for AF [22, 28]. To overcome this disadvantage, various derivatives of GGA have been synthesised, with improved pharmaco-chemical and HSP-boosting properties (Fig. 4a). Some of these derivatives also showed cardioprotective effects in tachypaced HL-1 cardiomyocytes (Fig. 4b). In the HALT&REVERSE project, we will test whether these derivatives reveal improved cardioprotective effects compared with GGA and elucidate their mode of action. In addition, one of the selected GGA derivatives will be further tested in an animal model for AF. Finally, GGA has also been tested in patients undergoing cardiac surgery, and atrial tissue will be used to test whether GGA induces HSP expression in patients and protects against post-surgery AF.Fig. 4


The future of atrial fibrillation therapy: intervention on heat shock proteins influencing electropathology is the next in line.

Lanters EA, van Marion DM, Steen H, de Groot NM, Brundel BJ - Neth Heart J (2015)

Geranylgeranylacetone (GGA) derivatives induce HSP70 expression and reveal cardioprotective effects. a Western blot showing induction of HSP70 levels in HL-1 cardiomyocytes treated with GGA and some of the GGA derivatives (Nyk compounds). b Representative calcium transient tracers of non-treated and normally paced (1 Hz) HL-1 cardiomyocytes (Control) or tachypaced cardiomyocytes (TP, 5 Hz) without or with treatment of 10 µM GGA or GGA derivatives (Nyk compounds) as indicated. c Overview of the central concept of HALT&REVERSE. Atrial fibrillation (AF) naturally progresses in time (red line), which is rooted in the underlying electropathology. By pharmacological induction of HSP levels (blue arrow), we aim to halt or even reverse electropathology and consequently AF progression (green line)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: Geranylgeranylacetone (GGA) derivatives induce HSP70 expression and reveal cardioprotective effects. a Western blot showing induction of HSP70 levels in HL-1 cardiomyocytes treated with GGA and some of the GGA derivatives (Nyk compounds). b Representative calcium transient tracers of non-treated and normally paced (1 Hz) HL-1 cardiomyocytes (Control) or tachypaced cardiomyocytes (TP, 5 Hz) without or with treatment of 10 µM GGA or GGA derivatives (Nyk compounds) as indicated. c Overview of the central concept of HALT&REVERSE. Atrial fibrillation (AF) naturally progresses in time (red line), which is rooted in the underlying electropathology. By pharmacological induction of HSP levels (blue arrow), we aim to halt or even reverse electropathology and consequently AF progression (green line)
Mentions: Although protective effects with GGA were observed, an important disadvantage of GGA is its high LogP value, which is around 9, and therefore generally high dosages are required, as found in the dog studies for AF [22, 28]. To overcome this disadvantage, various derivatives of GGA have been synthesised, with improved pharmaco-chemical and HSP-boosting properties (Fig. 4a). Some of these derivatives also showed cardioprotective effects in tachypaced HL-1 cardiomyocytes (Fig. 4b). In the HALT&REVERSE project, we will test whether these derivatives reveal improved cardioprotective effects compared with GGA and elucidate their mode of action. In addition, one of the selected GGA derivatives will be further tested in an animal model for AF. Finally, GGA has also been tested in patients undergoing cardiac surgery, and atrial tissue will be used to test whether GGA induces HSP expression in patients and protects against post-surgery AF.Fig. 4

Bottom Line: Currently, no effective therapy is known that can resolve this damage.Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients.Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF.This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF.

View Article: PubMed Central - PubMed

Affiliation: Unit Translational Electrophysiology, Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.

ABSTRACT
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia accounting for one-third of hospitalisations. Treatment of AF is difficult, which is rooted in the progressive nature of electrical and structural remodelling, called electropathology, which makes the atria more vulnerable for AF. Importantly, structural damage of the myocardium is already present when AF is diagnosed for the first time. Currently, no effective therapy is known that can resolve this damage.Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients. Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF. However, it is still unclear whether induction of HSPs also prolongs the arrhythmia-free interval after, for example, cardioversion of AF.In this review, we discuss the role of HSPs in the pathophysiology of AF and give an outline of the HALT&REVERSE project, initiated by the HALT&REVERSE Consortium and the AF Innovation Platform. This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF.

No MeSH data available.


Related in: MedlinePlus