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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

Persistence of atrial fibrillation. Surface electrograms of paroxysms (upper panel) and persistent (lower panel) atrial fibrillation. Wave-maps constructed during these different types of maps are also shown. A wave-map shows individual fibrillation waves represented by colours according to their sequence of appearance. A previously described mapping algorithm was used to classify them into peripheral waves (entering the mapping area from outside the electrode array), breakthrough waves (appearing at the epicardial surface inside the mapping area) or discontinuous conduction waves (fibrillation waves starting with a delay of 13–40 ms from boundaries of other waves). Sites of epicardial breakthroughs are indicated by white asterisks; white arrows indicate direction(s) of expansion of epicardial breakthrough or discontinuous fibrillation waves. Peripheral fibrillation waves are indicated by black arrows
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Fig1: Persistence of atrial fibrillation. Surface electrograms of paroxysms (upper panel) and persistent (lower panel) atrial fibrillation. Wave-maps constructed during these different types of maps are also shown. A wave-map shows individual fibrillation waves represented by colours according to their sequence of appearance. A previously described mapping algorithm was used to classify them into peripheral waves (entering the mapping area from outside the electrode array), breakthrough waves (appearing at the epicardial surface inside the mapping area) or discontinuous conduction waves (fibrillation waves starting with a delay of 13–40 ms from boundaries of other waves). Sites of epicardial breakthroughs are indicated by white asterisks; white arrows indicate direction(s) of expansion of epicardial breakthrough or discontinuous fibrillation waves. Peripheral fibrillation waves are indicated by black arrows

Mentions: It is generally assumed that transition of short-lasting paroxysms of AF to long-lasting episodes that no longer terminate spontaneously over time corresponds to a progression from a trigger-driven to a substrate-mediated arrhythmia due to a combination of electrical, structural and contractile atrial remodelling (Fig. 1). Previous studies have demonstrated that alterations in the atrial microscopic structure impair intra-atrial conduction [6]. Spach et al. [7, 8] were the first to provide evidence that two-dimensional propagation is discontinuous in nature at a microscopic level (Fig. 2). In their experiments, variations in shape and amplitude of extracellular potential waveforms were studied when the direction of conduction was changed from longitudinal to transverse in relation to the fibre axis. They observed that in uniform anisotropic myocardium, the shape of the upstroke of the transmembrane action potential depended on the direction of propagation in relation to the fibre orientation. Fast conduction in the longitudinal direction was associated with a slow upstroke and a long τ-foot (time constant of the action potential representing voltage decay) and slow conduction in the transverse direction with a fast upstroke and a short τ-foot. Differences were explained by the anisotropic distribution of intercellular connections (gap junctions, connexions). This was confirmed in a goat model for sustained (2 months) AF, where persistence of AF was associated with a lower density and inhomogeneous distribution of gap junctions [9, 10]. Gap junctions along the fibre axis provide a low resistance to current flow that increases the space constant and hence the electrotonic current flow. Subsequently, the upstroke of the transmembrane potential in this direction decreases and the τ-foot increases. Due to the high resistance barriers in the transverse direction, the space constant is reduced and the electrotonic current is therefore smaller. This results in an increase in the upstroke of the transmembrane potential and a decrease in the τ-foot. Consequently, as the safety factor is lower during longitudinal conduction than during transverse conduction, conduction block is more likely to occur during longitudinal conduction [11].Fig. 1


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)

Persistence of atrial fibrillation. Surface electrograms of paroxysms (upper panel) and persistent (lower panel) atrial fibrillation. Wave-maps constructed during these different types of maps are also shown. A wave-map shows individual fibrillation waves represented by colours according to their sequence of appearance. A previously described mapping algorithm was used to classify them into peripheral waves (entering the mapping area from outside the electrode array), breakthrough waves (appearing at the epicardial surface inside the mapping area) or discontinuous conduction waves (fibrillation waves starting with a delay of 13–40 ms from boundaries of other waves). Sites of epicardial breakthroughs are indicated by white asterisks; white arrows indicate direction(s) of expansion of epicardial breakthrough or discontinuous fibrillation waves. Peripheral fibrillation waves are indicated by black arrows
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4446279&req=5

Fig1: Persistence of atrial fibrillation. Surface electrograms of paroxysms (upper panel) and persistent (lower panel) atrial fibrillation. Wave-maps constructed during these different types of maps are also shown. A wave-map shows individual fibrillation waves represented by colours according to their sequence of appearance. A previously described mapping algorithm was used to classify them into peripheral waves (entering the mapping area from outside the electrode array), breakthrough waves (appearing at the epicardial surface inside the mapping area) or discontinuous conduction waves (fibrillation waves starting with a delay of 13–40 ms from boundaries of other waves). Sites of epicardial breakthroughs are indicated by white asterisks; white arrows indicate direction(s) of expansion of epicardial breakthrough or discontinuous fibrillation waves. Peripheral fibrillation waves are indicated by black arrows
Mentions: It is generally assumed that transition of short-lasting paroxysms of AF to long-lasting episodes that no longer terminate spontaneously over time corresponds to a progression from a trigger-driven to a substrate-mediated arrhythmia due to a combination of electrical, structural and contractile atrial remodelling (Fig. 1). Previous studies have demonstrated that alterations in the atrial microscopic structure impair intra-atrial conduction [6]. Spach et al. [7, 8] were the first to provide evidence that two-dimensional propagation is discontinuous in nature at a microscopic level (Fig. 2). In their experiments, variations in shape and amplitude of extracellular potential waveforms were studied when the direction of conduction was changed from longitudinal to transverse in relation to the fibre axis. They observed that in uniform anisotropic myocardium, the shape of the upstroke of the transmembrane action potential depended on the direction of propagation in relation to the fibre orientation. Fast conduction in the longitudinal direction was associated with a slow upstroke and a long τ-foot (time constant of the action potential representing voltage decay) and slow conduction in the transverse direction with a fast upstroke and a short τ-foot. Differences were explained by the anisotropic distribution of intercellular connections (gap junctions, connexions). This was confirmed in a goat model for sustained (2 months) AF, where persistence of AF was associated with a lower density and inhomogeneous distribution of gap junctions [9, 10]. Gap junctions along the fibre axis provide a low resistance to current flow that increases the space constant and hence the electrotonic current flow. Subsequently, the upstroke of the transmembrane potential in this direction decreases and the τ-foot increases. Due to the high resistance barriers in the transverse direction, the space constant is reduced and the electrotonic current is therefore smaller. This results in an increase in the upstroke of the transmembrane potential and a decrease in the τ-foot. Consequently, as the safety factor is lower during longitudinal conduction than during transverse conduction, conduction block is more likely to occur during longitudinal conduction [11].Fig. 1

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