A recent research study conducted by the UC Davis School of Medicine has revealed significant variances at the cellular level between male and female mice suffering from heart failure with preserved ejection fraction (HFpEF).
These discoveries might have an impact on the treatment of HFpEF in women as opposed to men.
HFpEF is characterized by the heart muscle contracting normally, but the heart’s inability to completely relax and refill.Properly between heartbeats is important for the heart to function. Diastolic dysfunction can occur if the heart is stiff or if the contraction process doesn’t shut off quickly enough. A study found that diastolic dysfunction in female mice was due to altered heart filament proteins, while in male mice it was due to the slow removal of calcium from heart cells between heartbeats. This caused a slight contraction to persist between beats. The findings were published in Cardiovascular Research. “This study highlights the significance of researching both male and female populations,” said D.The study’s senior author, Ronald M. Bers, is the chair of the Department of Pharmacology and the Joseph Silva Endowed Chair for Cardiovascular Research at the UC Davis School of Medicine. Bers mentioned that if these same molecular differences between males and females also occur in obese diabetic patients with HFpEF, it could mean that the best treatment approaches for HFpEF in women might be different from those for men.
Heart failure occurs when the heart is unable to pump enough blood and oxygen to support the body. In the U.S., approximately 6.2 million people have heart failure, and the five-year mortality rate is around 50%. However, there are many factors that can influence this rate.The survival rate for people with heart failure is not very high, especially for those with HFpEF, which about half of heart failure patients have. HFpEF is more common in women than in men, and men with HFpEF are at a higher risk of cardiac arrhythmias and sudden cardiac death.
A “two-hit” mouse model was created by researchers to study HFpEF, combining obesity and diabetes as the two factors. They used mice that lacked a leptin receptor, a hormone that promotes satiety, to represent the first factor. This resulted in increased appetite and obesity in the mice.The animals were made obese and diabetic for the first factor, whereas for the second factor, mice were given an aldosterone infusion. Aldosterone, which is produced by the adrenal gland, leads to fluid retention when present in high levels.
This animal model, which exhibits both heart failure and diabetes, allows researchers to study the mechanisms of muscle contraction and relaxation in both male and female mice.
The research team, consisting of Christopher Y. Ko, Juliana Mira Hernandez, Donald M. Bers, Erin Y. Shen, and Bence Hegyi, is shown in front of their key findings on the screen.
The dysregulation of calcium and titin are highlighted in the study.
Calcium plays a crucial role in the activation of heart muscle cells, controlling both contraction and relaxation, as well as the heart’s electrical activity. Each time the heart beats, calcium enters the heart cell, leading to muscle contraction and driving the electric signal that coordinates the contraction of millions of heart muscle cells necessary for efficient pumping. After each beat, calcium is removed from the cell, allowing the heart to relax and fill up for the next beat.
In male mice with HFpEF, the process of removing calcium from the heart muscle cells was slowed down, which hindered the complete relaxation of the cells. This can have negative effects on heart function.
The study found that male mice with HFpEF had higher levels of abnormal heart rhythms, or arrhythmias, between beats. On the other hand, female mice with HFpEF showed normal calcium movements in and out of heart cells. However, the researchers noticed an increase in a shorter and stiffer form of titin (N2B), a protein that acts as a supportive spring in the heart. They also observed phosphorylation of titin and another heart filament protein, troponin I, which made the female heart cells functionally stiffer and harder to fill, despite normal calcium movements.The removal process was considered standard.
“This research demonstrates that there are different targets for drugs in males and females, and it will serve as a foundation for future experiments using sex-specific drugs in HFpEF,” said Bence Hegyi, an associate project scientist in the Bers Lab and co-senior author of the study. “It is possible that women with this type of HFpEF could benefit from drugs that decrease heart stiffness. Conversely, men with this type of HFpEF might see more benefits from drugs that improve calcium removal.”
Study Limitations
The researchers identified several limitations of the study. While the mice used in this study may accurately represent the situation in human HFpEF, further research is needed.A significant number of HFpEF patients with diabetes and obesity may not be accurately represented by this model. To understand different subpopulations with HFpEF, multiple animal models will be necessary. Further preclinical and clinical studies are required to fully realize the potential benefits of this research.
Additional authors from the UC Davis School of Medicine include Erin Shen, Christopher Ko, Emily Spencer, Daria Smoliarchuk, and Julie Bossuyt. Juliana Mira Hernandez from the UC Davis School of Medicine and the University of Antioquia, Medellin, Colombia; and Zaynab Hourani and Henk Granzier from the University of Arizona, Tucson.
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