A new study published in Progress of science shows that female and male hearts respond differently to the stress hormone norepinephrine. The study in mice may have implications for human heart disorders such as arrhythmias and heart failure and how the 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’s heart responds to hormones and neurotransmitters in real time. The mice were exposed to noradrenaline, also known as norepinephrine. Norepinephrine is both a neurotransmitter and a hormone associated with the body’s “fight or flight” response.
The results reveal that the hearts of male and female mice respond uniformly initially after norepinephrine exposure. However, some areas of the female heart return to normal more quickly than the male heart, resulting in differences in the heart’s electrical activity.
“The differences in electrical activity that we see are called repolarization in female hearts. Repolarization refers to how the heart resets between each beat and is closely associated with some types of arrhythmias,” said Jessica L. Caldwell, first author of the study. Caldwell is a postdoctoral fellow in the Department of Pharmacology at the UC Davis School of Medicine.
“We know that there are sex differences in the risk of certain types of arrhythmias. The study reveals a new factor that may contribute to the different 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 deaths of men and one in every 5 female deaths in 2020. Despite the impact on both sexes, cardiology research has largely been conducted on male subjects.
In this study, the researchers were interested in looking at factors that can contribute to arrhythmias. Arrhythmias are a type of heart disorder in which the electrical impulses that control the heartbeat do not work properly. They affect between 1.5% and 5% of the population.
The novel imaging system uses a mouse, called a CAMPER mouse, that has been genetically engineered to emit light during a very specific chemical reaction in the heart: cAMP binding.
The cAMP molecule (an abbreviation 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 using 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 reaction to norepinephrine in real time, along with changes in electrical activity.
This new imaging approach revealed the differences in cAMP breakdown in male and female mice and the associated differences in electrical activity.
Including female mice leads to discoveries
The researchers had not planned to study responses based on gender, according to Crystal M. Ripplinger, the study’s lead author. But the researchers began to see a pattern of different reactions, which led them to realize that the differences were based on gender.
Ripplinger, an electrical and biomedical engineer, is a professor in the Department of Pharmacology.
When he started his lab at the UC Davis School of Medicine more than a decade ago, he used exclusively male animals. That was the norm for most investigations at the time. But several years ago, he began to include both male and female animals in his studies.
“Sometimes the data between the two sexes is the same. But if the data starts to show variation, the first thing we do is look for sex differences. Using male and female mice has revealed clues about differences we never would have suspected. Researchers are realizing that you can’t extrapolate to both sexes by studying only one,” Ripplinger said.
She notes that with the current study, it’s not clear what the differences in cAMP and electrical activity might mean.
“The response in 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.
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.