A new mechanism links preamyloid oligomer formation in the myocyte stress response associated with atrial fibrillation.

Atrial fibrillation remains the most common clinical cardiac arrhythmia, affecting 1-2% of the population [1-6]. It is characterized by uncoordinated depolarization of the atria in an intermittent (paroxysmal or persistent AF) or constant (permanent AF) fashion [7]. AF leads to impaired atrial contraction and is associated with increased morbidity and mortality [8]. Underlying this arrhythmia are specific electrical phenomena controlled by a diverse set of remodeling mechanisms. These electrical phenomena are reentrant waves, rapidly firing ectopic foci, and rotors which in combination can lead to initiation and maintenance of a fibrillating wave pattern [9]. Much of current research has focused on identifying remodeling mechanisms that develop an AF-prone substrate. These mechanisms can be generally grouped into three types: electrical, structural, and autonomic which have been reviewed in greater detail elsewhere [10-12]. Electrical remodeling includes alterations in K+ currents, L-type Ca2+ currents, and gap junction function. Structural remodeling includes atrial fibrosis, size, and ultrastructure. Autonomic remodeling includes hyperinnervation of the atria and surrounding region as well as increased sympathovagal activity. Though research to date has revealed a detailed and complex view of remodeling in AF, the specific myocyte stressors that activate these remodeling mechanisms are less well understood. The factors contributing to initiation of AF include inflammation, cell death, oxidative stress, hypertrophy and fibrosis [10-12]. Human clinical studies as well as mouse models have provided strong evidence of AF secondary to cardiac disease, such as congestive heart failure (CHF) where many of these remodeling mechanisms are activated by the failing heart [13-15]. These mechanisms can also be activated by AF itself, i.e. “AF begets AF,” which leads to progressive worsening of the disease as the atrial substrate becomes more and more AF-prone [16]. In cases of AF occurring independent of other diseases, referred to as lone AF, an understanding of these triggering factors can be especially important. In the recent publication, “Reactive γ-Ketoaldehydes Promote Protein Misfolding and Preamyloid Oligomer Formation in Rapidly-Activated Atrial Cells,” Sidorova et al. identify a new molecular component that may link oxidative stress to the development of an AF-prone substrate [17]. Their study exploits a rapidly-paced atrial cell line model to to mimic early AF stress responses in order to highlight a major role for oxidative stress pathways in atrial myocytes involving γ-ketoaldehydes (γ-KA) in the formation of preamlyoid oligomers (PAO), which are soluble precursors to amyloid deposits.