Johns Hopkins researchers have discovered a new drug that may be useful in treating a heart rhythm condition called long QT syndrome.
The study was published on-line on June 28 in the Early Edition of the Proceedings of the National Academy of Sciences.
“It’s exciting, and we are lucky that the compound does what we hoped it would do,” states Min Li, Ph.D., professor of neuroscience at the Johns Hopkins School of Medicine.
Long QT syndrome, which results from genetic mutation or certain medications, can cause the heart to beat chaotically and the affected person to die suddenly. The chaotic heartbeat is due to abnormal electrical activity in the heart. In an electrocardiogram test, this abnormality appears as a wider-than-normal QT interval, a pattern of “hills” in a map of peaks and valleys corresponding to the heart contracting and relaxing.
The culprit for the abnormal electrical activity is dysfunction of either of two types of channels on the surface of heart muscle cells.
These channels normally grant potassium ions, which carry a positive electrical charge, to leave the cell, but in the case of long QT syndrome, they do not grant enough ions to leave before closing. Li and his team wanted to find a drug that would specifically coax one of these channels – the hERG channel – to stay open for a normal length of time, a tiny longer than 300 milliseconds.
Finding a drug that alters the channel’s activity was not hard, he claims. “The hERG channel is like a magnet. A lot of compounds bind to it and block it.” But finding one that keeps it open long enough took significant effort.
At any given time, the hERG channel can either be open, closed or inactivated. Before the researchers could search for a drug, they needed to find out whether, in long QT syndrome, the hERG channel toggles too quickly from open to closed or from open to inactivated.
To figure this out, they turned to an existing mathematical model that describes the electrical activity of heart muscle cells.
Using the model, the researchers produced a mathematical curve of electrical activity, whose hill shape mimicked that of heart muscle cells from a healthy individual, and another whose wider hill shape mimicked that of heart muscle cells from a long QT syndrome patient.
The very similar shapes of the modeled and experimental curves suggested that the model was a good one for their study.
Next, they took the model one step further by changing certain parameters in their equations, such as the voltage across a heart muscle cell, which helps determine whether the hERG channel is open.
The model predicted that changing the voltage at which the channel toggles from open to inactivated would make the wide curve – and the related long QT interval – from long QT syndrome patients look like the normal curve and normal QT interval from healthy individuals. Li and his team realized that in order to attempt to make the long QT not so long, they needed to find a drug that would produce this voltage change.
Using a state-of-the-art automated electrophysiology instrument, they had previously screened massive compound libraries and found small-molecule drugs that modify hERG channel activity, including several that activate the channel. They selected a potent small-molecule drug that had first been characterized in that study and, based on its biophysical properties, would likely produce the desired voltage change. The researchers then tested whether the drug actually produced the desired voltage change in cultured rodent cells engineered to contain many duplicates of the hERG channel. They found that, as predicted by the model, the drug changed the voltage at which the channel toggles from open to inactivated. It had no effect on other channels they tested that typically are found in heart muscle cells.
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Submited at Tuesday, July 31st, 2012 at 12:15 am on Uncategorized by admin
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