scholarly journals Full spectrum of clonal haematopoiesis‐driver mutations in chronic heart failure and their associations with mortality

2021 ◽  
Author(s):  
Katharina C. Kiefer ◽  
Sebastian Cremer ◽  
Evangelia Pardali ◽  
Birgit Assmus ◽  
Khalil Abou‐El‐Ardat ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Driver Mutations ◽  
Full Spectrum

scholarly journals Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure

2020 ◽  
Author(s):  
Wesley T Abplanalp ◽  
Sebastian Cremer ◽  
David John ◽  
Jedrzej Hoffmann ◽  
Bianca Schuhmacher ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cell ◽  
Chronic Heart Failure ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Mutation Carriers ◽  
Single Cell Rna Sequencing

Rationale: Clonal hematopoiesis (CH) driven by mutations of DNA methyltransferase 3a (DNMT3A) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A CH-driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Objective: To define subsets of immune cells mediating inflammation in humans using single-cell RNA-sequencing. Methods and Results: Transcriptomic profiles of peripheral blood mononuclear cells were analysed in N=6 HF patients harboring DNMT3A CH-driver mutations and N=4 patients with HF and no DNMT3A mutations by single-cell RNA-sequencing. Monocytes of HF patients carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared to monocytes derived from HF patients without DNMT3A mutations. Among the specific up-regulated genes were the prototypic inflammatory interleukin (IL) IL1B, IL6, IL8, the inflammasome NLRP3, and the macrophage inflammatory proteins CCL3 and CCL4 as well as resistin, which augments monocyte-endothelial adhesion. Silencing of DNMT3A in monocytes induced a paracrine pro-inflammatory activation and increased adhesion to endothelial cells. Furthermore, the classical monocyte subset of DNMT3A mutation carriers showed increased expression of T-cell stimulating immunoglobulin superfamily members CD300LB, CD83, SIGLEC12, as well as the CD2 ligand and cell adhesion molecule CD58, all of which may be involved in monocyte-T cell interactions. DNMT3A mutation carriers were further characterized by increased expression of the T-cell alpha receptor constant chain and Th1, Th2, Th17, CD8+ effector, CD4+ memory and Treg specific signatures. Conclusions: This study demonstrates that circulating monocytes and T-cells of HF patients harboring CH-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic heart failure.

scholarly journals Use of Natriuretic Peptides to Guide and Monitor Heart Failure Therapy

2012 ◽  
Vol 58 (1) ◽  
pp. 62-71 ◽  
Author(s):  
A Mark Richards ◽  
Richard W Troughton
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Natriuretic Peptides ◽  
Hospital Admissions ◽  
Systolic Heart Failure ◽  
Prognostic Indicators ◽  
Full Spectrum ◽  
Cardiac Natriuretic Peptides ◽  
Design Characteristics ◽  
And Function

Abstract BACKGROUND Plasma B-type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are independent prognostic indicators across the full spectrum of cardiovascular disease. Serial changes in plasma B-type cardiac natriuretic peptides parallel prognosis in chronic heart failure. Beneficial responses to medications and devices used in the treatment of heart failure are associated with decreases in plasma B-type peptide concentrations. This effect has led to the hypothesis that intensified treatment directed at reducing B-peptide concentrations may improve outcomes in heart failure. CONTENT The efficacy of serial measurements of plasma B-type peptides in guiding titration of therapy for chronic heart failure has been the subject of several randomized controlled trials reported in the peer-reviewed literature since 2000. These reports are summarized in this review. Trial design, characteristics of the heart-failure population studied, duration of follow-up, exact end points recorded, and target peptide concentrations pursued all differ somewhat between trials. In addition, in studies in which benefits were seen, the exact mechanisms mediating the improvements in outcome were unclear. However, an overall consistency is emerging that is supported by 2 metaanalyses. SUMMARY In aggregate the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B-type peptide measurements, used in conjunction with established clinical methods, is likely to reduce cardiac mortality and hospital admissions with heart failure, at least in patients with systolic heart failure who are younger than 75 years and relatively free of comorbidities.

DNMT3A clonal hematopoiesis-driver mutations are associated with profound changes in monocyte and T cell signatures in humans with heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Abplanalp ◽  
C Cremer ◽  
S Cremer ◽  
D John ◽  
D John ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cell ◽  
Chronic Heart Failure ◽  
Single Cell ◽  
Rna Sequencing ◽  
Driver Mutations ◽  
Funding Source ◽  
Clonal Hematopoiesis ◽  
Mutation Carriers ◽  
Single Cell Rna Sequencing

Abstract Background Clonal hematopoiesis (CH) driven by mutations of DNA methyltransferase 3a (DNMT3A) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A CH-driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Single-cell RNA-sequencing provides a novel opportunity to define subsets of immune cells mediating inflammation in humans. Methods Transcriptomic profiles of peripheral blood mononuclear cells were analysed in N=6 HF patients harboring DNMT3A CH-drived mutations and with HF and N=5 patients with HF and DNMT3A mutations by single-cell RNA-sequencing. Results Monocytes of HF patients carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared to monocytes derived from patients with HF without DNMT3A mutations. Among the specific up-regulated genes were the prototypic inflammatory interleukins (IL) IL1B, IL6, and IL8, the macrophage inflammatory proteins CCL3 and CCL4 as well as restin, which augments monocyte-endothelial adhesion. The classical monocyte subset of DNMT3A mutation carriers showed increased expression of immunoglobulin superfamily members CD80, CD300LB, and SIGLEC12, as well as the cell adhesion molecule CD58, all of which may be involved in monocyte-T cell interactions. DNMT3A mutation carriers were further characterized by increased expression of T cell receptor chains and Th1, Th17, CD8+ and Treg specific signatures. Conclusions This study demonstrates that circulating monocytes and T cells of HF patients harboring CHIP-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic heart failure. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The German Research Foundation (SFB834, Project B1), and the German Center for Cardiovascular Research (DZHK).

Tailored therapy for heart failure: neurohormones

2011 ◽  
Vol 89 (8) ◽  
pp. 603-607 ◽  
Author(s):  
A. Mark Richards
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Prognostic Indicators ◽  
Full Spectrum ◽  
Clinical Methods ◽  
And Function

Plasma B type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are also powerful independent prognostic indicators across the full spectrum of cardiovascular disease. The efficacy of serial measurements of plasma B type peptides in guiding titration of therapy for chronic heart failure has been the subject of a number of randomized controlled trials. These are summarized in the following brief review. In the decade 2000–2010, 8 trials have been completed. Study design, the characteristics of the heart failure population studied, duration of follow-up, the exact end points recorded, and target peptide levels pursued all differ somewhat between trials. However, an overall consistency is emerging, supported by 2 metaanalyses. In aggregate, the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B type peptide measurements used in conjunction with established clinical methods is likely to reduce cardiac mortality and admissions with heart failure, at least in those patients aged under 75 years with impaired left ventricular systolic function.

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