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When the heart “gets out of line”

A dofetilide molecule of the hERG channel. Steffen Hering and his team investigated the effect of this substance on cardiac cells obtained by differentiation of human stem cells (Copyright: Anna Weinzinger).

Human stem cells help decipher mechanism for cardiac arrhythmia

When developing new drugs, it is important to rule out toxic effects on the heart. If a substance inhibits certain potassium channels in the heart muscle, the so-called hERG channels, occur with high probability cardiac arrhythmias. A team around the pharmacist Steffen Hering from the University of Vienna has now discovered that these rhythmic disturbances do not necessarily have to occur: if a calcium channel is “blocked” at the same time, damage to the heart can be prevented. Studies on cardiac cells from human stem cells played a key role. This opens the way for new innovations in drug development.

All guidelines for drug developments provide for studies on hERG channels, ie potassium channels in the heart muscle. If a substance blocks this ion channel, the drug development is usually terminated as unsuccessful. For more than 20 already approved medicines, it has been found over the last few years that they block HERG channels and cause fatal cardiac arrhythmias. These drugs had to be withdrawn from the market.

In contrast, some approved drugs inhibit hERG channels and still do not induce cardiac arrhythmias. The causes for these “exceptions” are little researched. An example of such a compatible hERG blocker is the active ingredient verapamil, which is used for the treatment of cardiac arrhythmias and hypertension.

Study on heart cells from human stem cells
Priyanka Saxena, A student of the doctoral program “Ion channels as Molecular Drug Targets” (“MolTag”), funded by the FWF at the University of Vienna, investigated the mechanism that makes hERG blockers harmless. It compared the inhibition of the hERG channels by dofetilide (a drug that can trigger severe arrhythmias and was therefore withdrawn from the market in 2004 in Europe) with 20 chemical derivatives (derivatives) of this substance. In collaboration with Godfrey Smith of the University of Glasgow, she investigated the effect of these substances on cardiac cells obtained by differentiation of human stem cells. Heart cells from human stem cells have gained high importance in the past for drug safety studies. It was found, That some of the dofetilide derivatives tested are safe and do not cause arrhythmias.

Mechanism with mathematics decrypted
A mathematical model, developed by Philipp Kügler at the University of Hohenheim, finally deciphered the underlying mechanism. “If a channel for calcium ions is additionally blocked, the arrhythmogenic effect of the hERG channel blockers can be lifted and the toxic effect on the heart can be prevented”, explains Steffen Hering from the Department of Pharmacology and Toxicology and spokesperson of the doctoral program: “The examinations of heart muscle cells from Human stem cells have been of great benefit. This work opens up new possibilities for pharmaceutical development in the pharmaceutical industry “.

 

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