Purkinje Fiber Ito β-Subunit Composition and IVF (p 1310)
Xiao et al suggest that aberrant currents in Purkinje fibers can cause ventricular arrhythmias.
Sudden cardiac death caused by ventricular fibrillation claims the lives of approximately 300,000 North Americans each year, and in nearly 10% of cases the cause is unknown, or idiopathic. Recently, members of a Dutch family with idiopathic ventricular fibrillation (IVF) were found to over-express transcripts of the DPP6 gene. Because the DPP6 protein modulates potassium channel kinetics and trafficking, Xiao and colleagues questioned whether high levels of DPP6 might actually affect potassium channel function and, in turn, cause arrhythmia. The team found that over-expression of DPP6 in canine heart tissue did indeed affect channel function, causing an increase in the density of transient outward potassium currents. Interestingly, this increase occurred in Purkinje cells, and ventricular myocytes were unaffected. While DPP6 was responsible for binding potassium channels in Purkinje cells, in ventricular cells a protein called KChIP2 performed this function, explaining the differing results. Computer modeling suggested that the increased current density in Purkinje cells would shorten their action potentials and initiate early repolarization as well, which would indirectly promp arrhythmia in adjacent ventricular myocytes. Altogether these findings have the potential to improve not only the understanding of ventricular arrhythmia mechanics, but possible arrhythmia treatments, as well.
Rapid Focal De-phosphorylation of Connexin43 (p 1334)
Huke et al discover how increased calcium sensitivity in cardiomyocytes can cause arrhythmia.
The increased sensitivity of cardiomyocytes to calcium has long been associated with hypertrophic cardiomyopathy, as well as other forms of heart disease. This extra sensitivity increases the risk of arrhythmia, and subsequently of sudden cardiac death. It is not clear how calcium sensitivity and arrhythmia are linked, but it is known that gap junctions—connections between neighboring cells—are crucial for the propagation of electrical currents across the myocardium. So Huke and colleagues examined gap junctions in myofilaments that were hypersensitive to calcium. They found that when these myofilaments were stressed, the gap junction protein Cx43 rapidly de-phosphorylated, causing conduction velocity to slow and neighboring cells to lose their electrical coupling—which would thus result in arrhythmia. Dephosphorylation of Cx43 was accompanied, and most likely caused, by depleted ATP levels in the immediate gap junction vicinity. This ATP depletion was perhaps due to the high energy requirements of calcium sensitive cells, the authors suggest. Whatever the reason, reversing calcium sensitivity prevented both localized ATP depletion and aberrant electrical conduction. This newly discovered proarrhythmic mechanism may help guide the development of antiarrhythmic therapies, say the authors.
HDL has Anti-Inflammatory Effects on Adipocytes (p 1345)
ApoA-I and HDL reduce inflammation in adipose tissue, report Umemoto et al.
Obesity is often associated with inflammation of the adipose tissues, which exacerbates insulin resistance and increases the risk of cardiovascular disease. The adipocytes are thought to recruit monocytes and macrophages via the generation of reactive oxygen species (ROS), which in turn promote the production of immune cell chemoattractants, such as monocyte chemotactic protein-1 (MCP-1) and serum amyloid A3 (SAA3). Both apoliporotein A-1 (apoA-1) and high density lipoprotein (HDL) are known to reduce inflammation in endothelial cells and macrophages, but their role in modulating inflammation in adipocyte tissue was unknown. Umemoto and colleagues show that in cultured adipocytes, ApoA-1 and HDL inhibit the production of reactive oxygen species which caused a reduction in gene expression of Mcp-1 and Saa3. Furthermore overexpression of human apoA-1 in mice fed a high-fat diet also reduced the recruitment of immune cells to adipose tissue. The new information provided in this paper should be helpful in guiding the design of therapies that prevent inflammation in adipose tissue, and thus the cardiovascular complications that go with it.
- © 2013 American Heart Association, Inc.