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Headlines:
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Back to Cardiology Articles
Monday, 3rd May 2004
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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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