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Heart failure–related atrial fibrillation: A new model for a new prevention strategy?

Heart failure–related atrial fibrillation: A new model for a new prevention strategy?

EDITORIAL COMMENTARY Heart failure–related atrial fibrillation: A new model for a new prevention strategy? Lance D. Wilson, MD,* Chia-Ti Tsai, MD, Ph...

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EDITORIAL COMMENTARY

Heart failure–related atrial fibrillation: A new model for a new prevention strategy? Lance D. Wilson, MD,* Chia-Ti Tsai, MD, PhD† From the *Heart and Vascular Research Center and the Departments of Emergency Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, and the †Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital. Atrial fibrillation (AF) complicates congestive heart failure (HF) in up to 40% of patients and is associated with worsening of HF, more frequent hospitalizations, and increased mortality.1,2 Atrial remodeling and interstitial fibrosis producing slow, heterogeneous conduction and predisposing to reentrant excitation is central to a proposed mechanism for the increased incidence of AF in HF.3,4 This mechanism has been suggested predominantly in large animal models of HF, such as canine pacing-induced HF5; and, there is evidence that conduction slowing, increased atrial refractoriness, and atrial fibrosis are frequently observed in HF patients with AF.4,6 HF is also associated with remodeling of connexins and sarcolemmel ionic currents both experimentally and in patients; however, these changes may not be as important for the development of AF in non-HF models (such as AF induced by rapid atrial pacing) in which decreased atrial refractoriness is important for the development of AF.4,7,8 Current HF treatments, which are designed to improve ventricular function and attenuate ventricular remodeling, have the additional effects of modulating atrial fibrosis and reducing the incidence of AF.9,10 However, further therapies designed to modify the arrhythmogenic substrate for AF, by attenuating or preventing HF-related fibrosis, are needed. The mechanism of atrial fibrosis in HF has yet to be fully elucidated, but candidates include (1) activation of the renin angiotensin system (RAS), potentially mediated by activation of the extracellular signal-regulated kinase (ERK) subfamily of the mitogen-activated protein kinase (MAPK),10 (2) reactive oxygen species,11 (3) transforming growth factor (TGF)-␤1,12 and (4) Janus kinase/signal transducers and activators of transcription pathways.13 In this issue of Heart Rhythm, in very carefully executed experiments, Shimano et al14 investigate the effects of pioglitazone, a peroxisome proliferators-activated receptor-␥ (PPAR-␥) activator, on the development of atrial fibrosis Address reprint requests and correspondence: Dr. Lance D. Wilson, Health and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, R 657 Cleveland, OH 44109; E-mail address: [email protected]

and AF in HF. PPAR-␥ is a transcription factor that regulates many physiologic functions, including glucose control and cell growth and differentiation. In a rabbit AF/HF model, Shimano et al demonstrate that pioglitazone attenuates atrial fibrosis and susceptibility to AF. The observed effect is similar to angiotensin receptor blockade (ARB) with candesarten or a combination of candesarten and pioglitazone. Analogous to what has been previously demonstrated for angiotensin II antagonism in an established canine pacing-induced AF/HF model, the drug’s effect was associated with a reduction in ERK activation. In addition, pioglitazone treatment was associated with reduced TGF-␤1 and TNF-␣ expression. Although PPAR-␥ activation has been demonstrated to decrease ventricular fibrosis in other models,15 evidence was previously lacking that PPAR-␥ activation could attenuate HF-related atrial fibrosis and AF and is an important finding. As discussed by Shimano et al, pioglitazone may be inhibiting atrial fibrosis in this model by inhibition of RAS with attenuated ERK activation and/or TGF-␤1 and TNF-␣ expression. Although data supporting the major observation (decreased atrial fibrosis) due to PPAR-␥ activation are convincing, the authors have demonstrated an association between a reduction in these signaling pathways and inflammatory cytokines and a reduction of fibrosis by PPAR-␥ agonist and not causality. Appropriately, the authors were careful not to suggest an established mechanism. It is interesting that the combined effects of ARB and PPAR-␥ activation did not have additional effects on atrial fibrosis or AF inducibility. The authors surmise that, despite targeting different receptors, ARB and PPAR-␥ activation are likely affecting the same downstream pathways. However, studies to define the precise cellular signal transduction systems and mechanism underlying this effect are needed.

A new AF model In this study, Shimano et al have developed and partially characterized an AF/HF model. Although tachypacing-induced HF in rabbits is an established model, it has not previously been applied to investigate mechanisms of AF.16 This model shows important similarities to the more estab-

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doi:10.1016/j.hrthm.2008.01.002

Wilson and Tsai

PPAR-␥ Activation and AF in Heart Failure

lished canine AF/HF models, including significant atrial fibrosis, conduction slowing, and susceptibility to AF. Although the duration of AF was brief, this is not necessarily unexpected due to the smaller rabbit atria. The model also shows similar early alteration in TGF-␤1 and TNF-␣ expression and MAPK activation as is observed in the canine model. This rabbit model has yet to be characterized regarding remodeling of atrial sarcolemmel ionic currents or connexin expression. This may be important to do, because during ventricular pacing, there may have been retrograde ventriculoatrial (VA) conduction, which was not well controlled for. Therefore, it is difficult for the authors to determine whether some of the electrophysiologic changes observed in the atria resulted from rapid atrial depolarization during retrograde VA conduction or was predominantly from downstream effects of mechanical stretch during left ventricular failure. In fact, the prior observations that atrial tachypacing alone shortens atrial refractoriness, HF without atrial tachypacing prolongs it, and the combination of atrial tachypacing and HF attenuates HF-induced prolongation of refractoriness5,8 (which may be what was observed in the study by Shimano et al) suggest there is an element of atrial remodeling due to rapid retrograde atrial pacing, which is opposed to the canine HF model that does not have retrograde VA conduction.5 The potential addition of retrograde conduction has implications for ionic remodeling and additional mechanisms for AF susceptibility in this model.8 Of note, ARB did not significantly improve clinical or echocardiographic signs of HF. Although this may support specific effects of both PPAR-␥ activation and ARB on atrial remodeling, independent of an effect on HF, the lack of demonstration of the well-known effects of angiotensin antagonism on clinical HF further suggests there may be differences between this model and larger animal models of HF that are yet to be determined.16

Clinical implications So should clinical investigations into pioglitazone and PPAR-␥ activators be proposed to prevent atrial remodeling in HF? The use of thiazolidinediones (like pioglitazone) in patients with HF has recently fallen under scrutiny. Although it does not appear that clinical fluid overload or HF was aggravated by pioglitazone in this animal model, this is a common observation in patients. Exacerbation of heart failure by thiazolidinediones is the major limitation of this class of drugs, although this remains controversial.17 Angiotensin antagonism provides protection against AF in HF patients, and if the two approaches do indeed have similar effects, as suggested by this study, PPAR-␥ activation using thiazolidinediones theoretically would not offer additional

461 benefit and only add risk of worsening HF. However, the general strategy of prevention of the substrate of AF, rather than rate or rhythm control with conventional antiarrhythmic agents, is an important paradigm for AF management in HF patients. The present study suggests the idea that in addition to angiotensin antagonism and statins, PPAR-␥ activators may someday represent another option for AF prevention.18

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