Study reveals gender-specific differences in HFpEF, guiding tailored treatment strategies for men and women.
Recent research from UC Davis School of Medicine has highlighted notable cellular-level differences in heart failure with preserved ejection fraction (HFpEF) between male and female mice. These discoveries may have significant implications for tailoring HFpEF treatments according to gender-specific differences.
HFpEF is characterized by the heart muscle’s inability to fully relax and properly refill with blood between beats, despite normal contraction. This condition, known as diastolic dysfunction, can arise if the heart muscle is excessively stiff or if the contraction process fails to cease promptly. The study revealed that female mice experienced diastolic dysfunction due to changes in heart filament proteins. In contrast, male mice exhibited dysfunction due to delayed calcium removal from heart cells, causing residual contraction between beats.
Published in Cardiovascular Research, these findings could lead to gender-specific HFpEF treatment strategies. According to Donald M. Bers, the chair of the Department of Pharmacology at UC Davis and a co-author of the study, if similar molecular differences are present in obese diabetic humans with HFpEF, it suggests that therapeutic approaches should vary for men and women.
Heart failure, a condition where the heart cannot pump sufficient blood and oxygen, affects approximately 6.2 million people in the United States. The five-year mortality rate for heart failure hovers around 50%, with various factors influencing survival outcomes. HFpEF accounts for about half of all heart failure cases, and women are nearly twice as likely to develop HFpEF compared to men. Men with HFpEF are often at higher risk for cardiac arrhythmias and sudden cardiac death.
Given the commonality of obesity and diabetes among HFpEF patients, researchers developed a unique “two-hit” mouse model to study the condition. The first factor involved using mice genetically engineered to lack leptin receptors. Leptin is a hormone that regulates satiety, and its absence leads to increased appetite, resulting in obesity and diabetes. The second factor involved administering aldosterone, a hormone produced by the adrenal gland that promotes fluid retention.
This innovative model, which mimics the development of HFpEF in the context of heart failure and diabetes, enabled researchers to explore the cellular and molecular dynamics of heart muscle contraction and relaxation in both male and female mice.
Calcium plays a pivotal role in heart muscle contraction and relaxation, as well as in the heart’s electrical activity. Each heartbeat involves calcium entering the heart cells, triggering contraction, and driving the electrical signal that synchronizes the contraction of millions of heart muscle cells. The removal of calcium from the cells at each beat allows the heart to relax and fill with blood for the next beat.
In male mice with HFpEF, calcium removal from heart cells was slowed, resulting in incomplete relaxation between beats and an increased occurrence of arrhythmias. Conversely, female mice exhibited normal calcium movement but showed increased levels of a shorter, stiffer form of the protein titin (N2B), alongside phosphorylation of titin and another filament protein, troponin I. These changes rendered the heart cells functionally stiffer, making the heart more difficult to fill despite normal calcium dynamics.
Bence Hegyi, an associate project scientist in the Bers Lab and co-senior author of the study, stated, “This research identifies different drug targets for males and females and could pave the way for future clinical trials with gender-specific targeted drugs for HFpEF.” Potentially, women with HFpEF might benefit from medications that reduce cardiac stiffness, whereas men might benefit more from drugs that enhance calcium removal.
The researchers acknowledged several limitations in their study. While the mouse model may represent a significant subset of HFpEF patients who are obese and diabetic, it may not encompass all HFpEF patients. Hence, multiple animal models are necessary to understand the different subpopulations within HFpEF. Further preclinical and clinical studies are essential to fully harness the potential benefits of these findings.
The research team included Erin Shen, Christopher Ko, Emily Spencer, Daria Smoliarchuk, and Julie Bossuyt from UC Davis School of Medicine; Juliana Mira Hernandez from UC Davis School of Medicine and the University of Antioquia, Colombia; and Zaynab Hourani and Henk Granzier from the University of Arizona, Tucson.
In summary, this study suggests that gender-specific therapeutic strategies could improve HFpEF treatment outcomes, recognizing the distinct cellular mechanisms at play in male and female heart failure patients.
Sources:
Female and male heart failure may require distinct treatments
Cause of common type of heart failure may be different for women and men
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