A new study published in scientific advances shows that female and male hearts react differently to the stress hormone norepinephrine. The study in mice could have implications for human heart conditions like arrhythmias and heart failure, and how different sexes respond to drugs.
The team built a novel fluorescence imaging system that allows them to use light to see in real time how a mouse heart responds to hormones and neurotransmitters. The mice were exposed to norepinephrine, also known as norepinephrine. Norepinephrine is both a neurotransmitter and a hormone associated with the body’s “fight-or-flight” response.
The results show that male and female mouse hearts initially respond uniformly to norepinephrine. However, some areas of the female heart normalize faster than the male heart, resulting in differences in the heart’s electrical activity.
“The differences in electrical activity that we observed are referred to as repolarization in the female hearts. Repolarization refers to how the heart resets between each heartbeat and is closely associated with some types of arrhythmias,” said Jessica L. Caldwell, first author of the study. Caldwell is a postdoctoral researcher in the Department of Pharmacology at UC Davis School of Medicine.
“We know that there are gender differences in the risk of certain types of arrhythmias. The study unveils a new factor that may contribute to differential susceptibility to arrhythmias between men and women,” Caldwell said.
Heart disease is the leading cause of death in the US
Heart disease is the leading cause of death for both men and women in the United States. It accounted for about 1 in 4 male deaths and 1 in 1 in 5 female deaths in 2020. Despite the impact on both sexes, cardiology research has been largely conducted in male subjects.
In this study, researchers were interested in investigating factors that may contribute to arrhythmias. Arrhythmias are a type of heart condition in which the electrical impulses that control the heartbeat don’t work properly. They affect between 1.5% and 5% of the population.
The novel imaging system uses a mouse called the CAMPER mouse, which has been genetically modified to emit light during a very specific chemical reaction in the heart – cAMP binding.
The cAMP molecule (an acronym for cyclic adenosine-3′,5;-monophosphate) is an intermediate messenger that converts signals from hormones and neurotransmitters, including norepinephrine, into heart cells.
The light signals from the CAMPER mouse are transmitted by a biosensor using fluorescence resonance energy transfer (FRET). This FRET signal can be acquired at high speed and with high resolution by a new imaging system designed specifically for the heart. This allows the researchers to record the heart’s response to norepinephrine and changes in electrical activity in real time.
This new imaging approach revealed the differences in the breakdown of cAMP in female and male mice and the associated differences in electrical activity.
Including female mice leads to discoveries
According to Crystal M. Ripplinger, senior author of the study, the researchers had not planned to study gender responses. But the researchers began to see a pattern of different responses, leading them to realize that the differences were gender specific.
Ripplinger, electrical and biomedical engineer, is a professor at the Institute of Pharmacology.
When she opened her lab at UC Davis School of Medicine over a decade ago, she used male animals only. That was the norm for most research at the time. But a few years ago, she began including both male and female animals in her studies.
“Sometimes the dates between the two sexes are the same. But if the data shows discrepancies, let’s look at gender differences first. Using male and female mice has revealed evidence of differences that we never would have guessed. “Researchers realize that you can’t extrapolate to both sexes by studying only one,” Ripplinger said.
She notes that in the current study, it’s not clear what the differences in cAMP and electrical activity might mean.
“The response in the female mice may or may not be protective. But simply documenting that there is a measurable difference in response to a stress hormone is significant. We hope to learn more in future studies,” Ripplinger said.
Additional authors of the study are I-Ju (Eric) Lee, Lena Ngo, Lianguo Wang, Donald M. Bers, Manuel F. Navedo and Julie Bossuyt of UC Davis; Sherif Bahriz of UC Davis and Mansoura University; Bing (Rita) Xu and Yang K. Xiang of UC Davis and VA Northern California.
This work was supported by grants from the National Institutes of Health, the American Heart Association, and the Veterans Administration Merit Grant.