Periodic Reporting for period 1 - CHIP-AVS (Clonal hematopoesis of indeterminate potential and degenerative aortic valve stenosis)
Berichtszeitraum: 2022-11-01 bis 2025-04-30
Degenerative aortic valve stenosis (AS) is the most common acquired heart valve disease, expected to rise due to an aging population. It currently lacks medical therapies to slow its progression, with surgical or transcatheter valve replacement (TAVR) being the only treatments. Without intervention, the condition’s two-year mortality rate approaches 50% after symptoms develop. While general risk factors for AS exist, predicting who will progress to severe disease remains challenging.
This project aims to uncover how genetic mutations, specifically in the DNMT3A gene—a driver of clonal hematopoiesis (CH)—impact the progression of AS, prognosis, cardiac fibrosis reversibility after TAVR, and links to cellular senescence and inflammaging. By using advanced single-cell and omics technologies, as well as state-of-the-art imaging and biosignature analyses, we hope to unravel the immune-mediated complexities of calcified aortic valve disease (CAVD).
This project aims to uncover how genetic mutations, specifically in the DNMT3A gene—a driver of clonal hematopoiesis (CH)—impact the progression of AS, prognosis, cardiac fibrosis reversibility after TAVR, and links to cellular senescence and inflammaging. By using advanced single-cell and omics technologies, as well as state-of-the-art imaging and biosignature analyses, we hope to unravel the immune-mediated complexities of calcified aortic valve disease (CAVD).
In the first funding period, the following major aims were achieved:
1. Novel Discoveries in Immune Cells: We developed a cutting-edge technique, MutDetect-Seq, to analyze the effects of DNMT3A mutations at the single-cell level. Our findings showed that immune cells with these mutations, such as monocytes and T cells, drive inflammation and calcification of the aortic valve through pro-inflammatory signaling and secretion of osteogenic factors like OSM and S100A9.
2. Insights into Myocardial Fibrosis: We demonstrated that DNMT3A mutations intensify interactions between immune cells and cardiac fibroblasts, leading to cardiac fibrosis. These findings may lead to novel anti-fibrotic therapies for patients with AS.
3. Prognostic Biomarkers: We identified senescence-associated secretory phenotype (SASP) markers, such as GDF-15, ICAM-1, and osteoprotegerin, as strong predictors of long-term mortality after TAVR, offering a new avenue for risk stratification.
4. New Research on Loss of Y Chromosome: We found that loss of the Y chromosome (LOY) in immune cells is associated with poorer outcomes in AS and kidney disease, linking this genetic phenomenon to age-related pathologies.
These achievements not only deepen our understanding of AS, but also point toward biomarkers and potential therapeutic targets, offering hope for personalized treatments for high-risk patients.
1. Novel Discoveries in Immune Cells: We developed a cutting-edge technique, MutDetect-Seq, to analyze the effects of DNMT3A mutations at the single-cell level. Our findings showed that immune cells with these mutations, such as monocytes and T cells, drive inflammation and calcification of the aortic valve through pro-inflammatory signaling and secretion of osteogenic factors like OSM and S100A9.
2. Insights into Myocardial Fibrosis: We demonstrated that DNMT3A mutations intensify interactions between immune cells and cardiac fibroblasts, leading to cardiac fibrosis. These findings may lead to novel anti-fibrotic therapies for patients with AS.
3. Prognostic Biomarkers: We identified senescence-associated secretory phenotype (SASP) markers, such as GDF-15, ICAM-1, and osteoprotegerin, as strong predictors of long-term mortality after TAVR, offering a new avenue for risk stratification.
4. New Research on Loss of Y Chromosome: We found that loss of the Y chromosome (LOY) in immune cells is associated with poorer outcomes in AS and kidney disease, linking this genetic phenomenon to age-related pathologies.
These achievements not only deepen our understanding of AS, but also point toward biomarkers and potential therapeutic targets, offering hope for personalized treatments for high-risk patients.
The technical advancement to detect the specific gene signature of mutant vs. wild-type cells is a major breakthrough, as it does not only give mechanistic insights, but may also provide for novel, unexpected therapeutic interventions. This most likely will also lead to generation of IPR (patent application is pending).
The specific interaction of mutant cells with activation of cardiac fibroblasts for the first time provides a rational explanation for the increased mortality associated with DNMT3A-CHIP-driver mutations even after successful removal of the calcified aortic valve. Thus, tailored anti-fibrotic therapies may offer personalized intervention in patients after successful removal of the stenotic valve.
The novel identification of loss of the Y chromosome in circulating immune cells, the most common acquired mutation in men, to contribute to profibrotic gene signatures of circulating immune cells suggests an important interaction between DNMT3A-CHIP driver gene harboring and age-associated chromosomal alterations in men, which might represent an entirely novel and unexpected risk factor for cardiovascular diseases in general.
The specific interaction of mutant cells with activation of cardiac fibroblasts for the first time provides a rational explanation for the increased mortality associated with DNMT3A-CHIP-driver mutations even after successful removal of the calcified aortic valve. Thus, tailored anti-fibrotic therapies may offer personalized intervention in patients after successful removal of the stenotic valve.
The novel identification of loss of the Y chromosome in circulating immune cells, the most common acquired mutation in men, to contribute to profibrotic gene signatures of circulating immune cells suggests an important interaction between DNMT3A-CHIP driver gene harboring and age-associated chromosomal alterations in men, which might represent an entirely novel and unexpected risk factor for cardiovascular diseases in general.