A new study published in Scientific Progress Female and male hearts show a different response to the stress hormone noradrenaline. The mouse study may have implications for human heart disorders such as arrhythmias and heart failure and how different sexes respond to medications.
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 noradrenaline, also known as norepinephrine. Noradrenaline is a neurotransmitter and hormone associated with the body’s “fight or flight” response.
The results show that the hearts of male and female mice initially respond similarly after exposure to noradrenaline. However, some areas of the female heart return to normal faster than the male heart, causing differences in the heart’s electrical activity.
“The differences in electrical activity we observed are called repolarization in women’s hearts. Repolarization refers to how the heart resets between each heartbeat and is closely linked to several types of arrhythmias,” said Jessica L. Caldwell, first author of the study. Caldwell is a postdoctoral scholar in the Department of Pharmacology at the UC Davis School of Medicine.
“We know that there are gender differences in the risk for certain types of arrhythmias. The study reveals a new factor that may contribute to different arrhythmia susceptibility between men and women,” said Caldwell.
Heart disease is the leading cause of death in the US
Heart disease is the leading cause of death for men and women in the United States. It accounted for about 1 in 4 male deaths and 1 in every 5 female deaths in 2020. Despite the impact on both genders, cardiology research has mostly been conducted on male subjects.
In this study, the researchers were interested in looking at factors that could contribute to arrhythmias. Arrhythmias are a type of heart disorder where the electrical impulses that control heartbeats do not function properly. They affect somewhere between 1.5% to 5% of the population.
The new imaging system uses a mouse, called the CAMPER mouse, that has been genetically modified to emit light during a very specific chemical reaction in the heart — cAMP binding.
The molecule cAMP (abbreviation for cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that converts signals from hormones and neurotransmitters, including noradrenaline, into action from heart cells.
The light signals from the CAMPER mouse are transmitted by a biosensor that uses fluorescence resonance energy transfer (FRET). This FRET signal can be picked up at high speed and resolution by a new imaging system specifically designed for hearts. This allows the researchers to record the heart’s reaction to noradrenaline in real time, as well as changes in electrical activity.
This new imaging approach revealed the differences in cAMP breakdown in female and male mice and the associated differences in electrical activity.
Findings come from including female mice
The researchers did not intend to study responses based on sex, according to Crystal M. Ripplinger, senior author of the study. But the researchers began to see a different pattern of 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 the UC Davis School of Medicine more than a decade ago, she used only male animals. That was the norm for most research at the time. But several years ago, she began to include male and female animals in her studies.
“Sometimes the data between the two sexes is the same. But if the data starts to show a difference, the first thing we do is look at gender differences. By using male and female mice we have given clues as to differences which we would never have suspected. Noting that you can’t extrapolate to both sexes from studying one,” Ripplinger said.
She notes that with the current study, it is not clear what the differences between cAMP and electrical activity might mean.
“The response in female mice may be protective – or it may not be. But it is significant to document that there is a measurable difference in the response to stress hormone. We hope to learn more in future studies, ” said Ripplinger.
Additional authors on the study include I-Ju (Eric) Lee, Lena Ngo, Lianguo Wang, Donald M. Bers, Manuel F. Navedo and Julie Bossuyt of UC Davis; Sherif Bahriz from 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.