Excess in Atherosclerotic and Inflammametabolic Diseases Are Differentially Expressed in Myelodysplasia and Are Highly Dependent on Age, R-IPSS and Ethnicity
Authors: Rivero Gustavo A. , Perli Elias , Moreno Stephanie , Salemi Jason L , Salemi Jason L 
Published: October 2019

Abstract
Background Myelodysplastic syndrome (MDS) is an inflammatory heterogeneous group of myeloid disorders with variable risk for acute myeloid leukemia (AML) conversion. Recent reports highlight that mutations [i.e. TET2, DNMT3A, AXSL1] configurate not only risk for malignant conversion in "healthy elderly individuals" but also 'directly' participate in coronary artery disease [CAD] development. TET2 clonal hematopoiesis [TET2 CHIP] accelerates atherosclerosis in mice via monocytic inflammatory amplification. Indeed, germ-line DNMT3A human disease phenocopy obesity and neurocognitive abnormalities suggesting that a more complex, but still poorly characterized cardiometabolic risk, probably originates from patient predisposition and somatic mutation acquisition. We seek to originate a cross-sectional "proof of concept" for quantifying the association between myelodysplasia [a clonal disorder initiated by CHIP mutations] and several systemic inflammatory conditions [i.e. CAD, peripheral vascular disease (PVD), obesity, depression and COPD].
Methods: A cross-sectional analysis of a nationally-representative sample of inpatient hospitalizations in the United States between 2007 and 2015 [750,249 MDS-related hospitalizations, or 83,361 hospitalizations per year] was performed to identify co-occurring inflammatory diseases during hospitalizations in patients older than 35 years, in which MDS was documented. Given the inflammatory nature of the disease, subgroups were defined to investigate the prevalence of individual inflammatory domains (per 1,000 MDS-related hospitalizations) according to Revised-International Prognostic Score System [R-IPSS]. Subgroup analysis was performed for patients based on age (above and below 65 years), and race/ethnicity. Prevalence and confidence intervals [CI] were obtained for each inflammatory condition. "Relevant" inflammatory domains were considered statistically significant based on non-overlapping 95% CIs.
Results: In examined admissions, prevalence for CAD in (Low-risk) LR- MDS age <> 65 was 12.2 vs 24.7, PVD 21.8 vs 60.2, [Fig 1 A and B] obesity 88.1 vs 51.7, major depression 14.6 vs 5.3, COPD 42.1 vs 70.7, p=0.0001 for all comparisons [Fig 1 B and C]. Conversely, prevalence for CAD in (High-risk) HR MDS age <> 65 was 9.1 vs 17.3, p=0.04; PVD 14.5 vs 43.2, p=0001; obesity 73.7 vs 42.2, p=0.003 major depression 5.1 vs 6.9, p=0.04 and COPD 23.0 vs 34.6, p=0.05. Differential prevalence expression for CAD was observed between non-Hispanic Whites (W) and Hispanics (H) [22 vs 28, p=0.02]. PVD was more prevalent, in both W vs H [64.6 and 52.2, p= 0.0002] and NH-Blacks/African Americans (AA) vs H [63.1 vs 52.2, p= 0.009]. Obesity was more prevalent among AA and H [64.1 and 62.9, respectively] than in W [51.9, p=0.009 for W vs AA and p=0.0002 for W vs H]. Similar expression for diabetes was observed between H vs W [404 vs 282, p<0.0001], H vs AA [404 vs 364, p=0.0001], and AA vs W [364 vs 282, p=<0.0001]. COPD was dominant among W and AA [73.8 and 78.4] as compared with H [50.4, p=0.0001 for H vs W and H vs AA]. Idiopathic pulmonary fibrosis was dominant in W and H [1.8 and 1.9] in comparison to AA [0.9, p=0.04 AA vs H and p=0.02 AA vs W]. Major depression prevalence was observed in AA, W and H in 5.4 vs 9.5 vs 14.3, respectively, p=0.0001 H vs AA and H vs W].
Conclusions. Prevalence of systemic inflammatory diseases in MDS are associated with age, disease biology [Low vs High risk] and ethnicity. Cardiopulmonary complications, such as PVD+ COPD are dominant in W and AA. Lower prevalence for PVD and COPD, but high rates for CAD, depression, diabetes and IPF in H vs W and AA suggest that ethnicity could differentially drive cardiometabolic and inflammametabolic phenotypes when co-occurring with clonal hemopoietic disorders such as MDS.

Disclosures
No relevant conflicts of interest to declare.