Genes may be targets to treat right heart failure linked to PAH

Study's focus: Genes that regulate the heart's electrical properties

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Certain genes are differentially expressed, meaning they have different activity, in people with pulmonary arterial hypertension (PAH) whose right side of the heart fails to work as it should, a study found.

Researchers believe that those genes, generally involved in regulating the electrical properties of the heart’s muscle cells, called cardiac myocytes, could provide possible targets to treat right heart failure.

“We hope to identify potential drug therapies that target [heart right side] arrhythmias,” or irregularities, the team wrote.

The study, “Electrical Remodeling in Right Ventricular Failure Due to Pulmonary Hypertension: Unraveling Novel Therapeutic Targets,” was published in the International Journal of Molecular Sciences.

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PAH occurs due to a narrowing of the blood vessels that supply the lungs. Such narrowing causes blood pressure to rise, which makes the heart work harder to pump blood.

Heart failure is when the heart fails to pump as much blood as the body needs each time it beats. When this occurs, the heart tries to compensate, or make up for it — for example, by beating faster or pumping more blood with each beat.

For this to happen, the heart’s electrical system changes, to speed up the rate at which those cardiac myocytes or muscle cells contract. Sometimes, this can cause the heart to beat irregularly, which is called an arrhythmia. But over time, compensation can contribute to enlarge the heart and further make heart failure worse.

Now, three researchers in the U.S. — from the department of anesthesiology and perioperative medicines at UCLA, in California — set out to learn why this happens and to help identify potential therapies.

To do this, they looked at the transcriptome of the right ventricle — the heart’s right lower chamber. It is responsible for pumping blood through to the lungs. The transcriptome is its full set of messenger RNA, a type of molecule that carries the genetic information needed to make proteins.

The team focused on 115 genes that have to do with ion channels, which are passageways through which ions flow in and out of cells. This movement can generate the electrical signals needed for cardiac myocytes to contract.

The study included 22 people with PAH: half with compensation of the right ventricle and the other half with decompensation. The participants’ right hearts’ transcriptome was compared with that of 17 healthy (control) individuals whose data were available from a public database.

There were 56 differentially expressed genes between patients with decompensated right ventricles and controls, the researchers found. Between patients with decompensated versus compensated right ventricles, there were 45.

The activity of genes coding for calcium and sodium ion channels was significantly lower in those with decompensated right ventricles, which could contribute to arrhythmias. There also were differences in genes coding for potassium ion channels.

Next, the researchers looked at animal models of PAH, and found there were similar changes in the genes involved in regulating these channels. That suggests they are a common feature of the disease.

Computer modeling was used to identify existing medications with the potential to reverse these changes in gene expression and treat arrhythmias in people with decompensated right ventricles.

Data-driven drug repurposing … predicted drug candidates that may reverse the altered gene expression.

While the modeling “predicted poor therapeutic potential of common anti-arrhythmic drugs in treating PAH-related arrhythmias,” three other types of potential medications were identified. They were Bruton’s tyrosine kinase inhibitors, TRPP antagonists, and beta-adrenergic receptor agonists.

“Data-driven drug repurposing using the channelome signature of PAH patients with decompensated RV failure predicted drug candidates that may reverse the altered gene expression,” the team wrote. The channelome refers to the set of ion channels.

With these findings, the researchers “hope to further facilitate investigation of arrhythmias using the appropriate preclinical PAH models and to identify new anti-arrhythmic drugs for PAH patients.” 

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