Dozens of commonly used drugs, including antibiotics, antinausea and anticancer medications, have a potential side effect of lengthening the electrical event that triggers contraction, creating an irregular heartbeat, or cardiac arrhythmia called acquired Long QT syndrome. While safe in their current dosages, some of these drugs may have a more therapeutic benefit at higher doses, but are limited by the risk of arrhythmia.
Through both computational and experimental validation, a multi-institutional team of researchers has identified a compound that prevents the lengthening of the heart’s electrical event, or action potential, resulting in a major step toward safer use and expanded therapeutic efficacy of these medications when taken in combination.
The team found that the compound, named C28, not only prevents or reverses the negative physiological effects on the action potential, but does not cause any change on the normal action potential when used alone at the same concentrations.
The results, found through rational drug design, were published online Friday, May 14 in the Proceedings of the National Academy of Sciences.
The research team was led by Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering at Washington University in St. Louis; Ira Cohen, MD, Ph.D., Distinguished Professor of Physiology and Biophysics, professor of medicine, and director of the Institute for Molecular Cardiology at the Renaissance School of Medicine at Stony Brook University; and Xiaoqin Zou, professor of physics, biochemistry, and a member of the Dalton Cardiovascular Research Center and Institute for Data Science and Informatics at the University of Missouri.
The drugs in question, as well as several that have been pulled from the market, cause a prolongation of the QT interval of the heartbeat, known as acquired Long QT Syndrome, that predisposes patients to cardiac arrhythmia and sudden death.
In rare cases, Long QT also can be caused by specific mutations in genes that code for ion channel proteins, which conduct the ionic currents to generate the action potential. Although there are several types of ion channels in the heart, a change in one or more of them may lead to this arrhythmia, which contributes to about 200,000 to 300,000 sudden deaths a year, more than deaths from stroke, lung cancer or breast cancer.
The team selected a specific target, IKs, for this work because it is one of the two potassium channels that are activated during the action potential: IKr (rapid) and IKs (slow).
“The rapid one plays a major role in the action potential,” said Cohen, one of the world’s top electrophysiologists. “If you block it, Long QT results, and you get a long action potential. IKs is very slow and contributes much less to the normal action potential duration.”
It was this difference in roles that suggested that increasing IKs might not significantly affect normal electrical activity but could shorten a prolonged action potential.
Cui, an internationally renowned expert on ion channels, and the team wanted to determine if the prolongation of the QT interval could be prevented by compensating for the change in current and inducing the Long QT Syndrome by enhancing IKs. They identified a site on the voltage-sensing domain of the IKs potassium ion channel that could be accessed by small molecules.
Zou, an internationally recognized expert who specializes in developing new and efficient algorithms for predicting protein interactions, and the team used the atomic structure of the KCNQ1 unit of the IKs channel protein to computationally screen a library of a quarter of a million small compounds that targeted this voltage-sensing domain of the KCNQ1 protein unit.
To do this, they developed software called MDock to test the interaction of small compounds with a specific protein in silico, or computationally. By identifying the geometric and chemical traits of the small compounds, they can find the one that fits into the protein – sort of a high-tech, 3-D jigsaw puzzle. While it sounds simple, the process is quite complicated as it involves charge interactions, hydrogen bonding and other physicochemical interactions of both the protein and the small compound.
“We know the problems, and the way to make great progress is to identify the weaknesses and challenges and fix them,” Zou said. “We know the functional and structural details of the protein, so we can use an algorithm to dock each molecule onto the protein at the atomic level.”
One by one, Zou and her lab docked the potential compounds with the protein KCNQ1 and compared the binding energy of each one. They selected about 50 candidates with very negative, or tight, binding energies.
Cui and his lab then identified C28 using experiments out of the 50 candidates identified in silico by Zou’s lab. They validated the docking results by measuring the shift of voltage-dependent activation of the IKs channel at various concentrations of C28 to confirm that C28 indeed enhances the IKs channel function. They also studied a series of genetically modified IKs channels to reveal the binding of C28 to the site for the in silico screening.
Cohen and his lab tested the C28 compound in ventricular myocytes from a small mammal model that expresses the same IKs channel as humans. They found that C28 could prevent or reverse the drug-induced prolongation of the electrical signals across the cardiac cell membrane and minimally affected the normal action potentials at the same dosage. They also determined that there were no significant effects on atrial muscle cells, an important control for the drug’s potential use.
“We are very excited about this,” Cohen said. “In many of these medications, there is a concentration of the drug that is acceptable, and at higher doses, it becomes dangerous. If C28 can eliminate the danger of inducing Q-T prolongation, then these drugs can be used at higher concentrations, and in many cases, they can become more therapeutic.”
While the compound needs additional verification and testing, the researchers say there is tremendous potential for this compound or others like it and could help to convert second-line drugs into first-line drugs and return others to the market.
With assistance from the Washington University Office of Technology Management, they have patented the compound, and Cui has founded a startup company, VivoCor, to continue to work on the compound and others like it as potential drug candidates.
The work was accelerated by a Leadership and Entrepreneurial Acceleration Program (LEAP) Inventor Challenge grant Washington University in St. Louis in 2018 funded by the Office of Technology Management, the Institute of Clinical and Translational Sciences, the Center for Drug Discovery, the Center for Research Innovation in Biotechnology, and the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship.
“This work was done by an effective drug design approach: identifying a critical site in the ion channel based on understanding of structure-function relation, using in silico docking to identify compounds that interact with the critical site in the ion channel, validating functional modulation of the ion channel by the compound, and demonstrating therapeutic potential in cardiac myocytes,” Zou said. “Our three labs form a great team, and without any of them, this would not be possible.”
The heart has an electrical system that allows it to contract in a rhythm. A key aspect of this electrical system is depolarization and repolarization. The electrical activity is conducted through the sinoatrial (SA) node and atrioventricular (AV) node and into the ventricles. This electrical activity is clearly outlined on an electrocardiogram (ECG) with P waves, the QRS complex, and T waves. The P wave represents the electrical activity of the atrium. The QRS complex shows the depolarization of the ventricles. Lastly, the T wave shows the repolarization of the ventricles.
The focus of this article is on the QT interval. It is measured from the Q wave until the T wave, and the QT interval clinically represents the repolarization of the ventricles. When measured on an ECG, the QT interval lengthens when the heart is beating slower and shortens when the heart is beating faster. That is why an adjusted version of the QT interval is used: QTc. This allows for an accurate QT interval at lower and higher heart rates. There are different formulas used to obtain the QTc interval.
Bazett is the most commonly used formula and is done by dividing the QT interval by the square root of the R-R interval. Fridericia is a similar formula, except it uses the cube root of the R-R interval. Framingham is a more complex formula, but the literature has shown it may be the most superior formula.
Bazett’s is automatically calculated on most ECG machines, and its limitations are underestimation and overestimation of the QTc in the cases of bradycardia and tachycardia, respectively. Its accuracy is largely limited to heart rates of 60 to 100 beats per minute, and clinicians must factor in the heart rate when assessing the QTc.
A normal QTc in a male is 440 ms or less, and in a female, it is 460 ms or less. Those with prolonged QT are at risk for one of the potentially deadly arrhythmias known as torsades de pointes. It is the most common form of polymorphic ventricular tachycardia, an unstable cardiac rhythm. This rhythm may cease on its own and go into sinus rhythm, or it may degenerate into ventricular fibrillation. The most common symptom is syncope.
Patients with torsade are administered a 2-4g bolus of magnesium sulfate and must undergo cardioversion if hemodynamically unstable. Isoproterenol can also be used to increase the heart rate, thereby decreasing the absolute QT interval. It is generally accepted that QT prolongation past 500 ms carries an increased risk of torsades de pointes; however, if the QT prolongation is severely prolonged, ventricular fibrillation is a certainty.
Prolonged QT Etiologies
- Long QT syndrome
- Jervell and Lange-Neilson syndromes
- Romano-Ward syndrome
Literature has shown that people who have diabetes and those suffering from certain inflammatory diseases may suffer from mildly prolonged QT. This is also true in those with heart disease. No major evidence in the general population indicates changes in mortality are associated with QT prolongation. However, subsets of cardiac patients may have an increased risk of mortality if they suffer from QT prolongation.
Pharmacological agents are the most common cause of QT prolongation given the broad range of medications that may induce it. As well, torsade, which is drug-induced, is reversible by the discontinuation of the offending drug.
- Antipsychotics: Haloperidol, ziprasidone, quetiapine, thioridazine, olanzapine, risperidone
- Antiarrhythmics: Amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide
- Antibiotics: Macrolides, fluoroquinolones
- Antidepressants: Amitriptyline, imipramine, citalopram, amitriptyline
- Others: Methadone, sumatriptan, ondansetron, cisapride
A vast number of medications prolong the QT interval. They are preferably classified based on the degree of QT prolongation they induce. This is specifically medication dependent. Caution is advised when combining QT-prolonging medications or when using these medications in those with electrolyte abnormalities.
Many commonly used medications, such as diphenhydramine and azithromycin, exhibit QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant caution in healthy patients. These medications bind to the human ether-related gene (hERG) channels and reduce electrical conduction through the potassium ion channels. This results in delayed repolarization of the heart.
Mechanism of Action
The QT interval is measured from the beginning of the QRS complex to the end of the T wave. Mechanisms that prolong the action potential duration can prolong the QT interval. Specifically, this occurs via delaying the third phase of repolarization. When the hERG channels are altered, there are changes made to the potassium ion channels. This causes an impairment of the channel’s ability to conduct electrical activity. The result is prolonged cardiac repolarization.
This mechanism can occur via genetic changes to hERG and/or drug-binding to these channels. Different drugs will induce changes in the hERG channels to variable degrees. Hence, different medications induce different levels of QT prolongation.
QT prolongation increases the risk of torsades de pointes, a potentially lethal arrhythmia. Torsades de pointes is the most common form of polymorphic ventricular tachycardia; it is initiated when a premature ventricular contraction occurs in the setting of a prolonged QT interval. This is known as the “R on T” phenomenon. It may cease on its own and return to sinus rhythm, or it may degenerate into ventricular fibrillation.
The clinical feature of this arrhythmia is often syncope. However, it can be asymptomatic. If it degenerates into ventricular fibrillation, death is the likely outcome if there is no intervention.
Patients diagnosed with long QT syndrome or any genetic causation of prolonged QT syndrome should use these medications with caution. Patients with hypokalemia, hypomagnesemia, and hypocalcemia should be put on QT-prolonging medications with caution. Certain electrolyte derangements prolong QT, which would be further exacerbated by these medications.
Medication interactions are another form of dangerous contraindication. Certain QT-prolonging medications are substrates of the cytochrome P450 (CYP450) system. If a patient is using a CYP450 inhibitor medication at the same time, there is a risk of significantly greater QT prolongation.
Patients using medications that prolong the QT interval should ideally be monitored with an ECG. Some medications induce minimal QT prolongation, and if there is no preexisting QT prolongation, then monitoring is unnecessary. A normal QTc in men is 440 ms or less, and in women, it is 460 ms or less. It is ideal to have patients within those parameters when on a QT-prolonging medication. A longer QTc is tolerated until it approaches and/or exceeds 500 ms.
The monitoring of electrolytes, specifically potassium, magnesium, and calcium, should be done in patients who have QT prolongation. The risk of further QT prolongation and torsades de pointes is increased when electrolyte abnormalities coexist with these medications.
reference link: https://www.ncbi.nlm.nih.gov/books/NBK534864/
reference link : More information: Yangyang Lin et al. Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2024215118