A UCLA-led research team has found that a gene mutation that affects insulin signaling in the heart may raise the risk of deadly abnormal heart rhythms in a subset of patients with cancer and could have implications for those with diabetes and obesity. The results of their work were online Sept. 10 in Circulation.
“This study is the first to link abnormalities in cardiac insulin signaling to the increased risk of cardiac arrythmias,” said co-senior author Dr. E. Dale Abel, William S. Adams distinguished professor, chair of the department of medicine at David Geffen School of Medicine, and executive medical director at UCLA Health. “These observations open up new possibilities for treating and preventing potentially lethal cardiac arrhythmias in susceptible individuals.”
Like people with coronary artery disease, patients with cancer and people with metabolic disorders such as obesity and diabetes are at increased risk of sudden cardiac death due to heart rhythm abnormalities, or arrhythmias, called ventricular tachycardia and ventricular fibrillation. Earlier studies by the Abel lab prior to its relocation to UCLA found evidence that the absence of a protein called insulin receptor substrate protein-2 (IRS2), which regulates how insulin affects the heart, could be the culprit: When their hearts were stressed by increased blood pressure, mice with a non-functioning IRS2 gene develop severe ventricular dysfunction and heart failure.
Given that the IRS2 gene is mutated in about 3% of all cancers, the team from UCLA and the University of Iowa wondered if patients whose cancer has an IRS2 gene mutation are more likely to have heart problems. To find out, they analyzed an anonymized clinical dataset containing information from approximately 200 million patients across 160 health care organizations, including genetic data on patients with cancer. Those whose cancer had IRS2 mutations were not only at greater risk of any cardiac complications, but were two to three times more likely to develop a dangerous cardiac arrhythmia like ventricular tachycardia.
To better understand the link between IRS2 dysfunction and ventricular arrhythmias, the researchers developed a mouse model whose heart cells lacked a functional IRS2 gene. When the mice were subject to sudden stress or reduced blood flow to the heart, they developed much more severe ventricular tachycardia than control mice. Analysis of heart cells from the mice with a non-functioning IRS2 gene showed abnormal patterns of calcium signaling, a cause of rhythm disturbances. This suggested that, in the absence of IRS2, the heart is more vulnerable to abnormal arrhythmias caused by unusual calcium activity.
Additional experiments showed that when IRS2 is functioning normally in heart cells, it blocks a pathway that involves a protein called AKT1. Without IRS2 to suppress its activity, AKT1 alters how the heart handles calcium, which leads to ventricular arrhythmias. The researchers showed that treating mice with dysfunctional IRS2 with a drug that inhibits AKT1 activity prevented them from developing ventricular tachycardia.
These findings underscore insulin’s important role in heart rhythm function and shed light on IRS2 as key regulator of the heart’s response to stress. Studies that build upon this work will investigate whether the higher risk of ventricular arrhythmias observed in people with diabetes and obesity can also be linked to IRS2 dysfunction. Earlier research from the Abel lab has already shown that diabetes is associated with alterations to insulin signaling in the heart.
“These findings have implications for understanding and treating ventricular arrhythmia risk in this much larger population of at-risk individuals,” Dr. Abel said.
This work was conducted with colleagues from the University of Iowa, where Dr. Abel’s laboratory was formerly housed. Dr. Abel is also a member of the UCLA Health Jonsson Comprehensive Cancer Center. Study authors are Qian Shi, PhD; Jinxi Wang, PhD; Hamza Malik, MD; Xuguang Li, MD, PhD; Jennifer Streeter, MD, PhD; Jacob Sharafuddin, BA; Eric Weatherford, PhD; David Stein; Yuval Itan, PhD; Biyi Chen, MD, PhD; Duane Hall, PhD; and Long-Sheng Song, MD, MS. It was supported by funding from the National Heart, Lung and Blood Institute and the American Heart Association.
