Mechanisms of Constitutive IKACh in AF (p 1031)
Makary et al suggest a scheme for stopping the perpetual progression of atrial fibrillation.
Atrial fibrillation, the most common form of heart arrhythmia, is associated with fibrosis and remodeling of the atria, which in turn worsens the arrhythmia. This positive feedback loop is thought to be in part caused by the activation of an inward constitutive potassium current in the cardiomyocytes. In vitro evidence shows that this current can be diminished by the activation of protein kinase C, but, counter-intuitively, PKC is activated in patients with atrial fibrillation – where the current is clearly not curbed. Using a dog model of the disease, Makary et al have now discovered that different isoforms of PKC inhibit or activate the potassium current. PKCα, which inhibits the potassium current, was down-regulated in the dog model cells, while PKCε, which the team showed activated the current, was relocated to the plasma membrane. It is possible that this relocation would put PKCε in the perfect place to directly phosphorylate the relevant potassium channel. Whatever the target of PKCε might be, inhibiting the activity of PKCε while boosting that of PKCα might be a strategy for tackling atrial fibrillation, say the team.
MSCs and Repair in Hibernating Myocardium (p 1044)
Injected stem cells induce resident cells to fix damaged hearts, say Suzuki et al.
Clinical trials using mesenchymal stem cells (MSCs) to improve heart function are currently underway. These trials follow numerous reports that MSCs can improve cardiac function in animal models of heart disease and myocardial infarction. It is unclear how the MSCs work, however. Some reports suggest that MSCs differentiate into cardiomyocytes, others that MSCs have paracrine effects, possibly inducing resident cardiomyoctes or stem cells to give rise to new myocytes. Suzuki et al injected MSCs into the coronary arteries of pigs with hibernating myocardium – heart tissue suffering chronic ischemia and hypertrophy, but still viable – and found that cardiomyocyte numbers increased, cellular hypertrophy was reduced, and contractility improved. The new myocytes were not MSC-derived, but apparently resulted from the mobilization and differentiation of endogenous bone marrow progenitors and the proliferation of resident myocytes. The success in improving function in this animal model, which lacks infarction, suggests that early intervention with stem cell therapy, before infarction and scarring occur, could be beneficial in heart disease patients. This concept broadens the potential indications for cell therapy.
Human Atrial AP Models (p 1055)
A new atrial myocyte model by Grandi et al is providing mechanistic insight into atrial fibrillation.
Treatment and management of atrial fibrillation, the most common human heart arrhythmia, is hindered by a lack of mechanistic knowledge about the condition. It is hoped that computer simulations of atrial myocyte electrophysiology might provide clues as to why the pathology arises and then persists. However, none of the atrial myocyte simulations have, to date, included adequate details of calcium regulation – which recent evidence suggests goes awry in atrial fibrillation. Grandi et al have now developed a new atrial myocyte model based on the model for ventricle myocytes they had previously developed. Importantly the new model incorporates the crucial atrial myocyte calcium-handling data. Cytosolic calcium bursts (transients) are reportedly reduced in atrial myocytes during atrial fibrillation, and this is associated with reduced muscle contractility. Analysis of the data using this model suggests that blocking a potassium current specifically expressed in atrial myocytes can restore calcium transients. This potassium current might therefore be a good target for enhancing contractility in patients with atrial fibrillation, suggest the authors.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.