Research Topics

Clonal hematopoeisis and inflammatory mechanisms in cardiovascular disease

Cardiovascular diseases (CVD) are the manifestations of chronic inflammation facilitated by aging, diabetes, dyslipidemia, hypertension, and smoking. These conditions promote atherosclerosis and fibrosis in the heart. Utilization of anti-inflammatory therapeutics can decrease death and mortality from cardiovascular disease and slow progression of heart failure. It therefore implicates inflammation to be causal in the development of CVD. As such, novel studies exploring the cardiovascular-immune interface are needed for improved therapeutic options.
 

One striking example of a condition that is causal fo
r CVD is clonal hematopoiesis of indeterminate potential (CHIP).  CHIP is a common age-related condition. CHIP occurs when a hematopoietic stem cell develops a somatic mutation in a driver gene that confers a survival or proliferative advantage to its daughter cells.  While there is no skewing of haematological lineages that develops from the mutation, a striking pro-inflammatory phenotype emerges. The mechanisms by which this happens remains unclear. It is also uncertain as to whether the mutated cells are causing the disease or whether these cells stimulate non-mutated cells to become more inflamed.
 

We are therefore explor
ing novel mechanisms in inflammation, which include cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, genetic susceptibility, obesity, and other stimulators of such events.
 

These studies require a highly multidisciplinary setting, including molecular biology, cardiology, hematology, genetics and bioinformatics.  Importantly, the advanced a
nd technical studies of clonal hematopoiesis of indeterminate potential and similar inflammatory mechanisms driving cardiovascular disease are uniquely suited to set the standards by which cardiology may utilize personalized medicine in the coming decades.

 

Dr. Wesley Abplanalp (Postdoc, Group leader)

Maximilian Merten (PhD student)

Bianca Schuhmacher (Research assistant)
 

Collaborations with Dept. of Cardiology 
Prof. Andreas Zeiher (MD, Director of cardiology at university hospital Frankfurt)

Dr. Sebastian Cremer (MD)

Dr. Silvia Mas-Peiro (MD)

 

 

 

References:

  1. Abplanalp WT, Cremer S, John D, Hoffmann J, Schuhmacher B, Merten M, Rieger MA, Vasa-Nicotera M, Zeiher AM, Dimmeler S. Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure Circ Res. 2021 Jan 22;128(2):216-228. doi: 10.1161/CIRCRESAHA.120.317104. Epub 2020 Nov 6.
  2. Abplanalp WT, John D, Cremer S, Assmus B, Dorsheimer L, Hoffmann J, Becker-Pergola G, Rieger MA, Zeiher AM, Vasa-Nicotera M, Dimmeler S. Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure. Cardiovasc Res. 2021 Jan 21;117(2):484-494. doi: 10.1093/cvr/cvaa101.
  3. Abplanalp WT, Mas-Peiro S, Cremer S, John D, Dimmeler S, Zeiher AM. Association of Clonal Hematopoiesis of Indeterminate Potential With Inflammatory Gene Expression in Patients With Severe Degenerative Aortic Valve Stenosis or Chronic Postischemic Heart Failure JAMA Cardiol. 2020 Jul 8;5(10):1-6. doi: 10.1001/jamacardio.2020.2468. Online ahead of print
  4. Assmus B, Cremer S, Kirschbaum K, Culmann D, Kiefer K, Dorsheimer L, Rasper T, Abou-ElArdat K, Herrmann E, Berkowitsch A, Hoffmann J, Seeger F, Mas-Peiro S, Rieger MA, Dimmeler S, Zeiher AM. Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. Eur Heart J. 2021 Jan 20;42(3):257-265. doi: 10.1093/eurheartj/ehaa845.
  5. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Abou-ElArdat K, Kiefer KC, Hoffmann J, Seeger F, Bonig H, Dimmeler S, Zeiher AM, Rieger MA. Hematopoietic alterations in chronic heart failure patients by somatic mutations leading to clonal hematopoiesis. Haematologica. 2020 Jul;105(7):e328-e332. doi: 10.3324/haematol.2019.224402. Epub 2019 Nov 7.
  6. Dorsheimer L, Assmus B, Rasper T, Ortmann CA, Ecke A, Abou-El-Ardat K, Schmid T, Brüne B, Wagner S, Serve H, Hoffmann J, Seeger F, Dimmeler S, Zeiher AM, Rieger MA. Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol. 2019 Jan 1;4(1):25-33. doi: 10.1001/jamacardio.2018.3965.
  7. Hoffmann J, Mas-Peiro S, Berkowitsch A, Boeckling F, Rasper T, Pieszko K, De Rosa R, Hiczkiewicz J, Burchardt P, Fichtlscherer S, Zeiher AM, Dimmeler S, Nicotera MV. Inflammatory signatures are associated with increased mortality after transfemoral transcatheter aortic valve implantation ESC Heart Fail. 2020 Oct;7(5):2597-2610. doi: 10.1002/ehf2.12837. Epub 2020 Jul 8.
  8. Mas-Peiro S, Hoffmann J, Fichtlscherer S, Dorsheimer L, Rieger MA, Dimmeler S, Vasa-Nicotera M, Zeiher AM. Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. Eur Heart J. 2020 Feb 21;41(8):933-939. doi: 10.1093/eurheartj/ehz591.
  9. Nicin L, Abplanalp WT, Mellentin H, Kattih B, Tombor L, John D, Schmitto JD, Heineke J, Emrich F, Arsalan M, Holubec T, Walther T, Zeiher AM, Dimmeler S. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts Eur Heart J. 2020 May 14;41(19):1804-1806. doi: 10.1093/eurheartj/ehaa311.
  10. Pardali E, Dimmeler S, Zeiher AM, Rieger MA. Clonal hematopoiesis, aging, and cardiovascular diseases. Exp Hematol. 2020 Mar;83:95-104. doi: 10.1016/j.exphem.2019.12.006. Epub 2019 Dec 29.

 

 

 

 

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