Heat Shock Protein–Inducing Compounds as Therapeutics to Restore Proteostasis in Atrial Fibrillation  Femke Hoogstra-Berends, Roelien A. M. Meijering, Deli Zhang, André Heeres, Lizette Loen, Jean-Paul Seerden, Irma Kuipers, Harm H. Kampinga, Robert H. Henning, and Bianca J. J. M. Brundel* 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 remod- eling 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 di- rected 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, pre- vent 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 perma- nent 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. (Trends Cardiovasc Med 2012;22: 62-68) © 2012 Elsevier Inc. All rights reserved. • Factors Underlying Atrial Fibrillation Initiation and Progression Atrial fibrillation (AF) represents the ar- rhythmia with the highest prevalence, accounting for one-third of hospitaliza- tions related to cardiac rhythm distur- bances (Dobrev et al. 2012). Because age is a main risk factor for developing AF, it is expected to place an increased (finan- cial) burden on societies as the popula- tion ages (Dobrev et al. 2012). In addi- tion to age, other conditions that limit cardiac or vascular performance are asso- ciated with AF, including cardiac surgery, valvular heart disease, congestive heart disease, ischemic cardiomyopathy, obe- sity, hypertension, and diabetes mellitus, causing atrial stretch and dilation (Dobrev et al. 2012). Although these adaptations in the atria provide a substrate for the ar- rhythmia, AF itself also promotes AF by inducing specific changes to cardiomyo- cytes. Together, these changes obstruct the effective conversion to sinus rhythm in AF patients (Dobrev et al. 2012). During the past decade, there has been increas- ing evidence that the expansion of irre- versible structural remodeling of cardio- myocytes is a main component of the progressive nature and the impaired functional recovery of AF (Figure 1) (Cha et al. 2004, Dobrev et al. 2012). However, current drug therapy, which mainly alleviates reversible electrical changes, has limited effect on patient outcome (Dobrev et al. 2012). Thus, ap- proaches that block the mechanisms conveying the AF-induced structural re- modeling, referred to as “upstream therapy,” may offer superior therapeu- tic outcomes. We found that the induc- tion of small heat shock proteins (HSPs) adequately suppresses the sub- strate for AF (Brundel et al. 2006b). Femke Hoogstra-Berends, Roelien A. M. Mei- jering, Deli Zhang, Robert H. Henning, and Bianca J. J. M. Brundel are at the Department of Clinical Pharmacology, University Institute for Drug Exploration (GUIDE), University of Groningen, University Medical Center Gro- ningen, 9713 AV Groningen, The Netherlands. Femke Hoogstra-Berends and Irma Kuipers are at Nyken BV, 9713 GX Groningen, The Nether- lands. André Heeres, Lizette Loen, Jean-Paul Seerden are at Syncom BV, 9747 AT Gro- ningen, The Netherlands. Harm H. Kampinga is at Cell Biology, Department of Radiation and Stress Cell Biology, University Institute for Drug Exploration (GUIDE), University of Gro- ningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands.  F. Hoogstra-Berends and I. Kuipers are em- ployees (technicians) of Nyken BV, which holds intellectual property interests in heat shock protein expression as a treatment in atrial fibril- lation. B. Brundel is CSO of Nyken BV. *Address correspondence to: Bianca J. J. M. Brundel, Department of Clinical Pharmacol- ogy, University of Groningen, UMCG, Deusing- laan 1, 9713 AV Groningen, The Netherlands. e-mail: B.J.J.M.Brundel@umcg.nl. Published online 3 August, 2012. © 2012 Elsevier Inc. All rights reserved. 1050-1738/$-see front matter 62 TCM Vol. 22, No. 3, 2012