Cell-Free DNA Profiles End-Organ Injury and Predicts Outcomes in Advanced Heart Failure With Left Ventricular Assist Device Implantation.

BACKGROUND

Adverse events after durable left ventricular assist devices (LVADs) pose a challenge to survival. However, there are limited risk stratification approaches. Plasma cell-free DNA (cfDNA) offers potential as a biomarker for assessing end-organ injury and risk stratification.

METHODS

The study included a multicenter prospective cohort of patients with heart failure with and without LVAD (cohort 1), a separate cohort of patients with heart failure with paired samples before and after LVAD (cohort 2) implantation, and a comparator group of healthy controls. Nuclear cfDNA (ncfDNA) and mitochondrial cfDNA were quantified by digital droplet polymerase chain reaction. Tissue-specific cfDNA was identified using whole-genome bisulfite sequencing. Differences in cfDNA levels by LVAD use were assessed with the Wilcoxon rank-sum test or the paired t test. Outcomes (hemocompatibility-related adverse event-free survival and infection-free survival) by cfDNA tertiles were compared by log-rank tests.

RESULTS

Cohort 1 had 76 patients with LVAD and 144 without LVAD. Cohort 2 had 40 patients with LVAD with samples before and after LVAD. ncfDNA levels were 4-fold higher (9794 versus 2386 copies/mL; P<0.001), and mtDNA was 1.5-fold higher (134 707 versus 82 054 copies/mL; P=0.01) in cohort 1 compared with healthy controls (n=48). Patients without LVAD had higher ncfDNA levels compared with those with LVAD in cohort 1 (11 423 versus 7912 copies/mL; P=0.019). After LVAD placement in cohort 2, ncfDNA nearly halved (18 980 versus 10 228 copies/mL; P<0.001), with significant reductions in innate immune, vascular endothelium, gastrointestinal, and liver cfDNA levels. The highest pre-LVAD tertile of ncfDNA was associated with worse infection-free (hazard ratio, 2.94 [95% CI, 1.31-6.56]; P=0.006) and hemocompatibility-related adverse event-free (hazard ratio, 3.24 [95% CI, 1.03-10.3]; P=0.034) survival.

CONCLUSIONS

LVAD implantation was associated with reductions in systemic and tissue-specific cfDNA levels. cfDNA levels offer promise for improving risk stratification of LVAD candidates for post-LVAD outcomes.