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Sex-Specific Human Cardiomyocyte Gene Regulation in Left Ventricular Pressure Overload
Lea Gaignebet1, Maciej M Kańduła2, Daniel Lehmann3
1Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.
Insights
Gene expression in male patients with aortic stenosis showed higher levels of structural and inflammation-related genes, impacting cardiac function differently than in female patients. These findings highlight sex-specific differences in pressure overload responses.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genomics
Background:
- Aortic stenosis (AS) is a significant cardiovascular condition.
- Sex-based differences in cardiovascular disease progression and response to therapy are increasingly recognized.
- Understanding cardiomyocyte-specific molecular changes in AS is crucial for targeted treatment.
Purpose of the Study:
- To investigate sex-based differences in gene expression within cardiomyocytes from patients with aortic stenosis.
- To test the hypothesis that maladaptive remodeling and inflammation-related genes are upregulated in male versus female AS patients.
- To explore the relationship between specific genes, cardiac function, and sex in AS.
Main Methods:
- Gene expression analysis of cardiomyocytes isolated from the interventricular septum of 34 patients undergoing aortic valve replacement.
- Collection of pre-operative clinical and echocardiographic data.
- Comparative analysis of gene expression and cardiac parameters between male and female patient cohorts.
Main Results:
- Male patients exhibited increased left ventricular end-diastolic diameter and posterior wall thickness, with lower ejection fraction compared to females.
- Most structural genes involved in cardiac hypertrophy and remodeling were expressed at higher levels in males.
- Two inflammation-related genes, CCN2 and NFKB1, showed a male-specific negative association with ejection fraction.
Conclusions:
- Novel insights into cardiomyocyte-specific molecular alterations driven by sex differences in pressure overload.
- A significant male-specific link between cardiac function and inflammation-related genes in aortic stenosis.
- Emphasizing sex differences in research and therapeutic strategies for aortic stenosis is essential for personalized medicine.
Objective:
To assess gene expression in cardiomyocytes isolated from patients with aortic stenosis, hypothesizing that maladaptive remodeling and inflammation-related genes are higher in male vs female patients.
Patients And Methods:
In this study, 34 patients with aortic stenosis undergoing aortic valve replacement from March 20, 2016, through May 24, 2017, at the German Heart Centre in Berlin, Germany, were included. Isolated cardiomyocytes from interventricular septum samples were used for gene expression analysis. Clinical and echocardiographic data were collected preoperatively.
Results:
Age, body mass index, systolic and diastolic blood pressure, comorbidities, and medication were similar between the 17 male and 17 female patients. The mean ± SD left ventricular end-diastolic diameter (52±9 vs 45±4 mm; P=.007) and posterior wall thickness (14.2±2.5 vs 12.1±1.6 mm; P=.03) were higher in male vs female patients, while ejection fraction was lower in male patients (49%±14% vs 59%±5%; P=.01). Focusing on structural genes involved in the development of cardiac hypertrophy and remodeling, we found that most were expressed higher in male vs female patients. Our modeling analysis revealed that 2 inflammation-related genes, CCN2 and NFKB1, were negatively related to ejection fraction, with this effect being male specific (P=.03 and P=.02, respectively).
Conclusion:
These findings provide novel insight into cardiomyocyte-specific molecular changes related to sex differences in pressure overload and a significant male-specific association between cardiac function and inflammation-related genes. Considering these sex differences may contribute toward a more accurate design of research and the development of more appropriate therapeutic approaches for both male and female patients.
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