Abstract
Abstract 10765: Plasma Cell-Free DNA Predicts Survival and Maps Tissue-Specific Sources of Injury in Pulmonary Arterial Hypertension
Circulation (New York, N.Y.), v 144(Suppl_1)
16 Nov 2021
Abstract
Abstract only
Background:
Cell-free DNA (cfDNA) is a non-invasive marker of tissue injury. Although being incrementally used as a clinical biomarker, its significance in pulmonary arterial hypertension (PAH) is unknown.
Methods:
Plasma cfDNA was isolated in two independent PAH cohorts (A, n=48; B, n=161) and healthy controls (n=48). Clinical variables and survival status were collected for Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL 2.0) scores and outcome determinations. Total cfDNA levels were compared amongst controls and PAH patients and also used to predict transplant-free survival. A subset of samples from cohort B (n=96) and controls (n=16) were subjected to bisulfite sequencing and methylation analysis to quantify tissue-specific sources of cfDNA.
Results:
Median (IQR) cfDNA concentrations were higher in cohort A PAH patients (exploratory cohort) compared to controls and increased according to REVEAL 2.0 risk group: controls 13.7 (10.8-18.8) vs low risk 14.4 (10.0-19.9) vs medium risk 14.6 (11.3-28.2) vs high risk 31.5 (17.2-45.6) ng/ml (P<0.01). cfDNA analysis in cohort B (validation cohort) demonstrated a similar cfDNA pattern: controls 13.7 (10.8-18.8) vs low risk 24.3 (16.0-57.9) vs medium risk 50.4 (29.4-70.9) vs high risk 51.5 (34.0-110.5) ng/ml (P<0.0001). cfDNA tertiles (Log-Rank; P=0.0001) and REVEAL 2.0 risk group (Log-Rank; P<0.0001) similarly predicted transplant-free survival, and the addition of cfDNA to REVEAL 2.0 improved model performance (AUC 0.64 to 0.70; P<0.05). Tissue-specific methylation analysis revealed increased cfDNA originating from vascular endothelium, cardiac myocytes, monocytes, erythrocyte progenitors, neutrophils, natural killer cells, and adipocytes (all P<0.005), but not colon, head/neck, liver, bladder, or kidney. With the exception of natural killer cells, cfDNA from enriched tissues also differentiated PAH patients of varying REVEAL 2.0 risk.
Conclusions:
cfDNA is elevated in PAH patients, correlates with disease severity and predicts worse survival. Methylation analysis of cfDNA in PAH patients is consistent with prevailing paradigms of disease pathogenesis. Thus, cfDNA may add prognostic power to PAH risk assessment and provide insight into disease progression.
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Details
- Title
- Abstract 10765: Plasma Cell-Free DNA Predicts Survival and Maps Tissue-Specific Sources of Injury in Pulmonary Arterial Hypertension
- Creators
- Samuel B Brusca - University of California, San FranciscoJason M Elinoff - National Institutes of HealthYvette Zou - National Institutes of HealthMoon K Jang - National Institutes of HealthHyesik Kong - National Institutes of HealthCumhur Y Demirkale - National Institutes of HealthJunfeng Sun - National Institutes of HealthFayaz Seifuddin - National Heart Lung and Blood InstituteMehdi Pirooznia - National Heart Lung and Blood InstituteHannah A Valantine - Stanford MedicineCarl Tanba - College Station Medical CenterAbhishek Chaturvedi - Virginia Commonwealth UniversityManreet Kanwar - Allegheny Health NetworkRaymond L Benza - The Ohio State UniversityIoana R Preston - College Station Medical Centersean agborenoh - National Heart Lung and Blood InstituteMichael A Solomon - National Institutes of Health
- Publication Details
- Circulation (New York, N.Y.), v 144(Suppl_1)
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- Cardiology
- Other Identifier
- 991021932105504721