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Back to Cardiology Articles

Monday, 3rd May 2004

 

JTV519 was tested in mice has been shown to prevent arrhythmias. It targets leaky calcium channels.

 
 

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A small-molecule drug may be capable of preventing arrhythmias according to a team of researchers at Columbia University Medical Center. The new drug called JTV519 has been developed and tested in mice. It targets leaky calcium channels. Heart arrhythmias, which are characterized by fast and erratic beating of the heart, can cause sudden death. This is particularly more common in people with heart failure or otherwise weakened hearts.

The Role of Calcium Channels

In the normal heart cell, the membrane surrounding a heart cell contains a small calcium channel that is stimulated by the electrical impulses that drive heart rhythm. When stimulated, this calcium channel triggers another, larger calcium channel within the cell, called the ryanodine receptor (RyR2), to release calcium ions. The rush of calcium ions then signals the heart muscle to contract powerfully. The ryanodine receptor sits at the surface of the sarcoplasmic reticulum, a sac containing calcium ions, and is the major gatekeeper for calcium ion release. The more calcium released through the ryanodine receptor, the stronger the contraction of the heart.

In a previous study, the same research team found that the calcium channels from patients with heart failure have defective function that, in addition to making them unresponsive to further stimulation by catecholamines, also causes a calcium leak that can weaken heart muscle contraction and possibly trigger fatal heart arrhythmias. These arrhythmias, known as ventricular fibrillation, are the cause of death in about 50 percent of patients with heart failure.

RyR2, is normally held closed by the interaction of another protein called calstabin2. When calstabin binds it, the channel does not open, and no calcium is released. But when the interaction of RyR2 and calstabin2 is disrupted, the channel begins to leak Ca2+, triggering arrhythmia.

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Study details

The research, led by Andrew Marks, MD, Director of the Center for Molecular Cardiology at Columbia University Medical Center, was set to investigate whether a drug known to enhance calstabin2 - ryanodine receptor binding could prevent the development of arrhythmias.

The experimental drug JTV519, a 1,4-benzothiazepine derivative, has recently been shown to reduce diastolic sarcoplasmic reticulum Ca2 leak in an animal model of heart failure. JTV519 was shown to increase binding of the protein calstabin2 to the ryanodine receptor hence the potential for blocking arrhythmias.

The study was conducted using mice which either had defective calstabin2 or had no calstabin2. Some of the mice were given the experimental drug. Both groups were then exercised to induce arrhythmias. The 10 mice that received the drug did not develop an arrhythmia, whereas 8 of 9 untreated mice died after arrhythmic events. The experimental drug had no effect on knockout animals that had no calstabin2 suggesting that calstabin2 presence is essential for drug to function. The drug blocked potentially fatal arrhythmias in these mice by stabilizing the crucial protein-protein interaction between RyR2 and calstabin and preventing Ca2+ leakage, Marks? team reports.

References

Xander H. T. Wehrens, Stephan E. Lehnart, Steven R. Reiken, Shi-Xian Deng, John A. Vest, Daniel Cervantes,3 James Coromilas,3 Donald W. Landry, Andrew R. Marks. Protection from Cardiac Arrhythmia Through Ryanodine Receptor?Stabilizing Protein Calstabin2. Science:304 April, 2004.

 

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