VUMC researchers find clue to drug-induced arrhythmiasFeb. 24, 2022, 9:45 AM
by Bill Snyder
Researchers at Vanderbilt University Medical Center have made a fundamental discovery about how the heart compensates for genetic variations that otherwise could trigger abnormal and potentially fatal heart rhythms.
Their findings, reported recently in the journal Circulation, add significantly to understanding what causes abnormal heart rhythms, or arrhythmias, and suggest that certain medications can induce them in susceptible people by overcoming the heart’s compensatory mechanism.
The existence of a compensatory mechanism has been postulated for more than 20 years, but until now, “there was no way to prove it,” said the paper’s first author, Yuko Wada, MD, PhD, a research fellow in Clinical Pharmacology.
“That heart cells somehow recognize they need to ‘fix’ their … ion currents in some way in order to stay normal — this is the first time we’ve seen that,” added the paper’s corresponding author, Dan Roden, MD, director of the John A. Oates Institute for Experimental Therapeutics.
The heart is both a muscle and an electrical generator. An electrical signal that travels from the top to the bottom of the heart stimulates the heart muscle to contract and pump blood through the body.
The electrical signal is generated and transmitted by changes in the flow of electrically charged atoms, called ions, through proteins called ion channels on the surfaces of heart muscle cells. The predominant ions in the heart are sodium and potassium.
The electrocardiogram (ECG) follows five electrical waves that produce the heartbeat. An abnormally long interval between the Q and T waves in the heart’s main pumping chambers, the ventricles, may signal an arrhythmia, or abnormal heart rhythm, which increases the risk for heart attack or sudden cardiac death.
More than 400 drugs are known to increase the QT interval, increasing the risk of arrhythmias. They include some antihistamines, diuretics, antibiotics, antidepressants, cholesterol-lowering and diabetes drugs and even some anti-arrhythmia medications.
Some, but not all drug-induced arrhythmias occur in people who have genetic variations, or variants, that affect the activity of the sodium channels in their heart muscle cells. Two common variants in the sodium channel gene — S1103Y and R1193Q — have been associated with drug-induced arrhythmias.
Fifteen percent of people of African ancestry carry the S1103Y variant, while 12% of people of East Asian ancestry carry the R1193Q variant. The commonality of these variants suggests that normally they do not affect the health of those who carry them, except in the presence of certain drugs.
To test this hypothesis, Wada and her colleagues created human heart muscle cells from stem cells isolated from blood samples, and with a genome editing technique called CRISPR/Cas9, inserted the S1103Y and R1193Q variants.
They then measured the electrical activity of the cells, the equivalent of the QT interval measured by the ECG. It was completely normal.
They also created heart muscle cells from the blood of people who carried the variants but had not taken arrhythmia-inducing drugs. Again, the electrical activity of the cells was normal — despite the fact that cells with a variant always showed an abnormal sodium current that should have prolonged electrical activity.
There was another unexpected finding: a potassium current, or flow of potassium ions, that normally signals the end of the heartbeat, was markedly increased in these cells. One interpretation is that the increased potassium current “compensates” for the abnormal sodium current. Certain drugs, however, blocked the compensatory mechanism, triggering arrhythmia.
The findings highlight the need to include ancestral diversity in genomic and pharmacogenomic studies, and to identify people with certain genetic variations who may be at increased risk of arrhythmia if they take drugs that inhibit the heart’s compensatory mechanisms.
The discovery raises another question: how many other genetic variations would cause abnormalities were it not for compensatory mechanisms? The combination of stem cell and genome editing techniques now makes it possible for researchers to find out.
Roden, who holds the Sam L. Clark, MD, PhD Endowed Chair, is professor of Medicine, Pharmacology and Biomedical Informatics, and Senior Vice President for Personalized Medicine at VUMC.
Other VUMC co-authors included Tao Yang, MD, PhD, Christian Shaffer, BS, Laura Daniel, PhD, Andrew Glazer, PhD, Giovanni Davogustto, MD, Brandon Lowery, BS, Eric Farber-Eger, BS, and Quinn Wells, MD, PharmD, MSCI.
The research was supported in part by National Institutes of Health grants HL149826 and HG010904, the Heart Rhythm Society and the American Heart Association.