A new signalling mechanism associated with the development of ventricular fibrillation, a kind of arrhythmia or irregular heartbeat, has been uncovered in a study headed by Guadalupe Sabio and Jose Jalife at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.
The findings of the study, which were published in the journal Nature Cardiovascular Research, offer hope for future therapy possibilities for this potentially fatal illness.
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The most common cause of sudden cardiac mortality is ventricular fibrillation. Although ageing is a known risk factor for the development of cardiac arrhythmia, the mechanisms behind this link have been difficult to pinpoint, impeding progress towards the development of specific treatments.
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The heartbeat is a series of regular contractions of the cardiac muscle that efficiently pumps blood throughout the body. A highly coordinated contraction of the heart muscle cells in a painstakingly choreographed pattern is required to achieve this. When an arrhythmia develops, the heart cycle accelerates and becomes erratic, potentially resulting in death.
The CNIC researchers established a link between the development of ventricular fibrillation and the activation of two critical signalling proteins, the stress kinases p38 and p38, using animal models. The relationship with these enzymes was irrespective of the animals' gender.
This revelation opens the door to new treatment options for this illness.
When the investigators investigated the hearts of aged mice, they discovered that p38 and p38 activation were enhanced.
A comparable increase in enzyme activity was reported in the hearts of mice with a hereditary or pharmacologically induced proclivity to develop ventricular arrhythmias. These findings imply that stress signalling via p38 and p38 is likely crucial in the development of this disease.
"When we found that activation of these p38 kinases was a shared feature of distinct arrhythmogenic situations, we realized that they likely play an important role that we needed to investigate," said first author Segun Rafael Romero.
An in-depth analysis of this signalling pathway revealed that when these protein kinases are activated they alter the electrical properties of cardiomyocytes (the heart's muscle cells), triggering the appearance of arrhythmias. This onset of arrhythmia involves p38-mediated alterations to specific ion channels that coordinate cardiomyocyte contraction.
The scientists found that p38g and p38d phosphorylate a receptor called ryanodine receptor 2 and another protein called SAP97, resulting in a mislocalization of the potassium ion channel Kv4.3. These molecular changes lead to premature ventricular activation and an increased susceptibility to ventricular fibrillation.
The study findings identify a promising therapeutic target for the development of new strategies to prevent sustained ventricular fibrillation and provide protection against this serious condition.
