title: Heat shock protein-inducing compounds as therapeutics to restore proteostasis in atrial fibrillation.
abstract: Atrial fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality and is expected to affect approximately 30 million North Americans and Europeans by 2050. AF is a persistent disease, caused by progressive, often age-related, derailment of proteostasis resulting in structural remodeling of the atrial cardiomyocytes. It has been widely acknowledged that the progressive nature of the disease hampers the effective functional conversion to sinus rhythm in patients and explains the limited effect of current drug therapies. Therefore, research is directed at preventing new-onset AF by limiting the development of substrates underlying AF promotion. Upstream therapy refers to the use of drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) and recurrence of the arrhythmia following (spontaneous) conversion and to prevent the progression of AF (secondary prevention). Recently, we observed that heat shock protein (HSP)-inducing drugs, such as geranylgeranylacetone, prevent derailment of proteostasis and remodeling of cardiomyocytes and thereby attenuate the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Also, correlative data from human studies were consistent with a protective role of HSPs in preventing the progression from paroxysmal AF to permanent AF and in the recurrence of AF. In this review, we discuss novel HSP-inducing compounds as emerging therapeutics for the primary and secondary prevention of AF.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Hoogstra-Berends
authors.forename: Roelien A M
authors.initials: RA
authors.lastname: Meijering
authors.forename: Deli
authors.initials: D
authors.lastname: Zhang
authors.forename: André
authors.initials: A
authors.lastname: Heeres
authors.forename: Lizette
authors.initials: L
authors.lastname: Loen
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Seerden
authors.forename: Irma
authors.initials: I
authors.lastname: Kuipers
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
mesh_terms: D001281:Atrial Fibrillation / Q000188:drug therapy / Q000473:pathology*; D018450:Disease Progression; D018840:HSP70 Heat-Shock Proteins / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000627:therapeutic use; D006801:Humans; D032383:Myocytes, Cardiac; D057165:Proteostasis Deficiencies / Q000188:drug therapy / Q000473:pathology*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; D006360:Heat-Shock Proteins