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Abstract
Atrial fibrillation (AF) is the most common, sustained clinical tachyarrhythmia associated with significant morbidity and mortality. AF is a persistent condition with progressive structural remodeling of the atrial cardiomyocytes due to the AF itself, resulting in cellular changes commonly observed in aging and in other heart diseases. While rhythm control by electrocardioversion or drug treatment is the treatment of choice in symptomatic AF patients, its efficacy is still limited. Current research is directed at preventing first-onset AF by limiting the development of substrates underlying AF progression and resembles mechanism-based therapy. Upstream therapy refers to the use of non-ion channel anti-arrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) or recurrence of the arrhythmia following (spontaneous) conversion (secondary prevention). Heat shock proteins (HSPs) are molecular chaperones and comprise a large family of proteins involved in the protection against various forms of cellular stress. Their classical function is the conservation of proteostasis via prevention of toxic protein aggregation by binding to (partially) unfolded proteins. Our recent data reveal that HSPs prevent electrical, contractile, and structural remodeling of cardiomyocytes, thus attenuating the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Furthermore, studies in humans suggest a protective role for HSPs against the progression from paroxysmal AF to persistent AF and in recurrence of AF. In this review, we discuss upregulation of the heat shock response system as a novel target for upstream therapy to prevent derailment of proteostasis and consequently progression and recurrence of AF.
Highlights
Our recent data reveal that Heat shock proteins (HSPs) prevent electrical, contractile, and structural remodeling of cardiomyocytes, attenuating the Atrial fibrillation (AF) substrate in cellular, Drosophila melanogaster, and animal experimental models
The findings suggest HSPA1A to play a role in inhibiting the development of a non-cardiomyocyte substrate for AF induction
HSPs increase SR Ca2+ ATPase activity and stimulate both the reuptake of Ca2+ into the SR and the extrusion of Ca2+ out of the cardiomyocyte via Na+/Ca2+ exchanger (Liu et al, 2006; Chen et al, 2010). These findings suggest that HSPs can protect against changes in calcium handling proteins, resulting in attenuation of AF progression
Summary
AF-induced derailment of proteostasis includes changes in ion channel function, kinomics, HDAC and calpain activation and underlies reversible electrical remodeling and irreversible structural remodeling and thereby AF initiation and progression. In tachypaced HL1 atrial cardiomyocytes and Drosophila melanogaster models for AF, a general HSP induction via a mild heat shock or by a HSPinducing drug GGA, conserved cardiomyocyte proteostasis during tachypacing and protected against subsequent electrical, contractile, and structural remodeling (Brundel et al, 2006a,b; Zhang et al, 2011a).
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