New drug shows promise for long QT syndrome
Artist rendition of the heart’s hERG channels opening
(Medical Xpress) -- 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 online on June 28 in the Early Edition of the Proceedings of the National Academy of Sciences.
Its exciting, and were lucky that the compound does what we hoped it would do, says 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 allow potassium ions, which carry a positive electrical charge, to leave the cell, but in the case of long QT syndrome, they dont allow 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 little longer than 300 milliseconds.
Finding a drug that alters the channels activity wasnt 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 large compound libraries and found small-molecule drugs that alter 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 copies 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.
The researchers then wanted to see if the drug had the same effect in human heart muscle cells containing a mutated gene that leads to fewer copies of the hERG channel. These cells are difficult to culture in a petri dish, so the researchers started with stem cells derived from the skin cells of a person with long QT syndrome. By adding specific hormones to these cells, they induced them to become heart muscle cells that contract rhythmically.
They have an incredibly synchronized behavior. Its like a wave in a stadium, says Li.
Using these cells, Li and his team performed an experiment similar to the previous one and found that the drug changed the voltage at which the channel toggles from open to inactivated. Moreover, it decreased the width of the hill-shaped curves, suggesting that it may be useful in treating long QT syndrome.
The next step, which Lis collaborators have started, is to test the drugs safety and efficacy in animals. If the drug is found to be safe and effective, it may eventually be tested in humans.
The results so far are pretty encouraging, says Li.
Journal reference: Proceedings of the National Academy of Sciences
Provided by Johns Hopkins University
- Keeping a beating heart in rhythm Mar 31, 2011 | not rated yet | 0
- Fever may trigger heart failure in patients with the genetic disease LQT-2 Jun 12, 2008 | not rated yet | 0
- Brain and heart link may explain sudden death in Rett Dec 14, 2011 | not rated yet | 0
- Study offers novel insight into cardiac arrhythmias, sudden cardiac death May 09, 2008 | not rated yet | 0
- Cardiac disease treatments could get help from patient-derived stem cells Jan 17, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
As the world prepares for what may be the next pandemic strain of influenza virus, in the H7N9 bird flu, a new UC Irvine study reveals that the 2009 H1N1 swine flu pandemic was deadliest for people under the age of 65, while ...
Diseases, Conditions, Syndromes 1 hour ago | not rated yet | 0
The World Health Organization says the Horn of Africa is experiencing an outbreak of polio with cases confirmed in Kenya and Somalia.
Diseases, Conditions, Syndromes 2 hours ago | not rated yet | 0
A man who had contracted the coronavirus has died in Saudi Arabia, raising the death toll in the kingdom from the SARS-like virus to 17, the health ministry announced on its website on Wednesday.
Diseases, Conditions, Syndromes 2 hours ago | not rated yet | 0
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
Diseases, Conditions, Syndromes 3 hours ago | not rated yet | 0 |
Patients with underlying heart failure are more likely to experience adverse outcomes from mild hypothyroidism, according to a recent study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & ...
Diseases, Conditions, Syndromes 4 hours ago | not rated yet | 0
(HealthDay)—For HIV-infected individuals with recurrent Clostridium difficile infection, fecal microbiota therapy is feasible, according to a letter published in the May 21 issue of the Annals of Intern ...
29 minutes ago | not rated yet | 0
(AP)—A federal panel of medical experts says that an experimental insomnia drug from Merck & Co Inc. appears safe and effective, despite evidence from company trials that the pill can cause daytime sleepiness and difficulty ...
39 minutes ago | not rated yet | 0
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
2 hours ago | 5 / 5 (1) | 0 |
(HealthDay)—Implementation of systematic monitoring for medication adherence will allow for identification of barriers to adherence and tailoring of interventions, according to a viewpoint piece published ...
1 hour ago | not rated yet | 0
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
2 hours ago | not rated yet | 1 |