New imaging system reveals how female and male hearts respond differently to stress hormone

A new study published in Scientists progress shows that female and male hearts react differently to norepinephrine, a stress hormone. The mouse study may have implications for human heart disorders like arrhythmias and heart failure and how different sexes respond to drugs.

The team built a new type of fluorescence imaging system that allows them to use light to see how a mouse heart responds to hormones and neurotransmitters in real time. The mice were exposed to norepinephrine, also known as norepinephrine. Noradrenaline is both a neurotransmitter and a hormone associated with the body’s “fight or flight” response.

The results reveal that male and female mouse hearts initially respond uniformly after exposure to norepinephrine. However, some areas of the female heart return to normal faster than the male heart, which produces differences in the electrical activity of the heart.

The differences in electrical activity that we observed are called repolarization in the heart of women. Repolarization refers to how the heart resets between each heartbeat and is closely related to certain types of arrhythmias.”

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 reveals a new factor that may contribute to different susceptibility to arrhythmia between men and women,” said Caldwell.

Heart disease is the leading cause of death in the United States

Heart disease is the leading cause of death for both men and women in the United States. It accounted for approximately 1 in 4 male deaths and 1 out of 5 female deaths in 2020. Despite the impact on both genders, cardiology research has largely been performed on male subjects.

In this study, researchers were interested in examining factors that may contribute to arrhythmias. Arrhythmias are a type of heart disorder where the electrical impulses that control the heartbeat don’t work properly. They affect somewhere between 1.5% to 5% of the population.

Methods

The new imaging system uses a mouse, called the CAMPER mouse, which has been genetically engineered to emit light in a very specific chemical reaction in the heart -; binding to cAMP.

The cAMP molecule (short for cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that converts signals from hormones and neurotransmitters, including norepinephrine, into action from heart cells.

Light signals from the CAMPER mouse are transmitted by a biosensor that uses fluorescence resonance energy transfer (FRET). This FRET signal can be captured at high speed and high resolution by a new imaging system specially designed for hearts. This allows researchers to record the heart’s response to norepinephrine in real time, as well as changes in electrical activity.

This new imaging approach revealed the differences in the distribution of cAMP in female and male mice and the associated differences in electrical activity.

Inclusion of female mice leads to discoveries

The researchers had not planned to study gender-based responses, according to Crystal M. Ripplinger, lead author of the study. But the researchers began to see a pattern of different reactions, which led them to realize that the differences were based on sex.

Ripplinger, an electrical and biomedical engineer, is a professor in the Department of Pharmacology.

When she started her lab at UC Davis School of Medicine more than a decade ago, she used exclusively male animals. This was the norm for most searches at the time. But several years ago, she began to include both male and female animals in her studies.

“Sometimes the data between the two sexes is the same. But if the data starts to show variations, the first thing we do is look at the differences between the sexes. Using male and female mice has revealed clues to differences that we never would have suspected. Researchers are realizing that you can’t extrapolate to both genders by just studying one,” Ripplinger said.

She notes that with the current study, it’s unclear what the differences in cAMP and electrical activity may mean.

“The response in female mice may be protective – or it may not. But simply documenting that there is a measurable difference in response to a stress hormone is significant. We hope to find out more in future studies,” said said Ripplinger.

Other study authors include 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.