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Association of Clonal Hematopoiesis of Indeterminate Potential With Inflammatory Gene Expression in Patients With Severe Degenerative Aortic Valve Stenosis or Chronic Postischemic Heart Failure.
Abplanalp, Wesley Tyler; Mas-Peiro, Silvia; Cremer, Sebastian; John, David; Dimmeler, Stefanie; Zeiher, Andreas M.
  • Abplanalp WT; Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.
  • Mas-Peiro S; Partner Site Frankfurt Rhine-Main, German Center for Cardiovascular Research, Berlin, Germany.
  • Cremer S; Department of Medicine, Cardiology, Goethe University Hospital, Frankfurt, Germany.
  • John D; Partner Site Frankfurt Rhine-Main, German Center for Cardiovascular Research, Berlin, Germany.
  • Dimmeler S; Department of Medicine, Cardiology, Goethe University Hospital, Frankfurt, Germany.
  • Zeiher AM; Partner Site Frankfurt Rhine-Main, German Center for Cardiovascular Research, Berlin, Germany.
JAMA Cardiol ; 5(10): 1170-1175, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-636079
ABSTRACT
Importance Cytokine release syndrome is a complication of coronavirus disease 2019. Clinically, advanced age and cardiovascular comorbidities are the most important risk factors.

Objective:

To determine whether clonal hematopoiesis of indeterminate potential (CHIP), an age-associated condition with excess cardiovascular risk defined as the presence of an expanded, mutated somatic blood cell clone in persons without other hematological abnormalities, may be associated with an inflammatory gene expression sensitizing monocytes to aggravated immune responses. Design, Setting, and

Participants:

This hypothesis-generating diagnostic study examined a cohort of patients with severe degenerative aortic valve stenosis or chronic postinfarction heart failure, as well as age-matched healthy control participants. Single-cell RNA sequencing and analyses of circulating peripheral monocytes was done between 2017 and 2019 to assess the transcriptome of circulating monocytes. Exposures Severe degenerative aortic valve stenosis or chronic postinfarction heart failure. Main Outcomes and

Measures:

CHIP-driver sequence variations in monocytes with a proinflammatory signature of genes involved in cytokine release syndrome.

Results:

The study included 8 patients with severe degenerative aortic valve stenosis, 6 with chronic postinfarction heart failure, and 3 healthy control participants. Their mean age was 75.7 (range, 54-89) years, and 6 were women. Mean CHIP-driver gene variant allele frequency was 4.2% (range, 2.5%-6.9%) for DNMT3A and 14.3% (range, 2.6%-37.4%) for TET2. Participants with DNMT3A or TET2 CHIP-driver sequence variations displayed increased expression of interleukin 1ß (no CHIP-driver sequence variations, 1.6217 normalized Unique Molecular Identifiers [nUMI]; DNMT3A, 5.3956 nUMI; P < .001; TET2, 10.8216 nUMI; P < .001), the interleukin 6 receptor (no CHIP-driver sequence variations, 0.5386 nUMI; DNMT3A, 0.9162 nUMI; P < .001;TET2, 0.5738 nUMI; P < .001), as well as the NLRP3 inflammasome complex (no CHIP-driver sequence variations, 0.4797 nUMI; DNMT3A, 0.9961 nUMI; P < .001; TET2, 1.2189 nUMI; P < .001), plus upregulation of CD163 (no CHIP-driver sequence variations, 0.5239 nUMI; DNMT3A, 1.4722 nUMI; P < .001; TET2, 1.0684 nUMI; P < .001), a cellular receptor capable of mediating infection, macrophage activation syndrome, and other genes involved in cytokine response syndrome. Gene ontology term analyses of regulated genes revealed that the most significantly upregulated genes encode for leukocyte-activation and interleukin-signaling pathways in monocytes of individuals with DNMT3A (myeloid leukocyte activation log[Q value], -50.1986; log P value, -54.5177; regulation of cytokine production log[Q value], -21.0264; log P value, -24.1993; signaling by interleukins log[Q value], -18.0710 log P value, -21.1597) or TET2 CHIP-driver sequence variations (immune response log[Q value], -36.3673; log P value, -40.6864; regulation of cytokine production log[Q value], -13.1733; log P value, -16.3463; signaling by interleukins log[Q value], -12.6547 log P value, -15.7977). Conclusions and Relevance Monocytes of individuals who carry CHIP-driver sequence variations and have cardiovascular disease appear to be primed for excessive inflammatory responses. Further studies are warranted to address potential adverse outcomes of coronavirus disease 2019 in patients with CHIP-driver sequence variations.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Aortic Valve Stenosis / Gene Expression / Clonal Hematopoiesis / Heart Failure Type of study: Cohort study / Observational study / Prognostic study Topics: Long Covid / Variants Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: JAMA Cardiol Year: 2020 Document Type: Article Affiliation country: Jamacardio.2020.2468

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Aortic Valve Stenosis / Gene Expression / Clonal Hematopoiesis / Heart Failure Type of study: Cohort study / Observational study / Prognostic study Topics: Long Covid / Variants Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: JAMA Cardiol Year: 2020 Document Type: Article Affiliation country: Jamacardio.2020.2468