RESUMO
Background: Cardiorespiratory fitness positively correlates with longevity and immune health. Regular exercise may provide health benefits by reducing systemic inflammation. In chronic disease conditions, such as chronic heart failure and chronic fatigue syndrome, mechanistic links have been postulated between inflammation, muscle weakness, frailty, catabolic/anabolic imbalance, and aberrant chronic activation of immunity with monocyte upregulation. We hypothesize that (1) temporal changes in transcriptome profiles of peripheral blood mononuclear cells during strenuous acute bouts of exercise using cardiopulmonary exercise testing are present in adult subjects, (2) these temporal dynamic changes are different between healthy persons and heart failure patients and correlate with clinical exercise-parameters and (3) they portend prognostic information. Methods: In total, 16 Heart Failure (HF) patients and 4 healthy volunteers (HV) were included in our proof-of-concept study. All participants underwent upright bicycle cardiopulmonary exercise testing. Blood samples were collected at three time points (TP) (TP1: 30 min before, TP2: peak exercise, TP3: 1 h after peak exercise). We divided 20 participants into 3 clinically relevant groups of cardiorespiratory fitness, defined by peak VO2: HV (n = 4, VO2 ≥ 22 mL/kg/min), mild HF (HF1) (n = 7, 14 < VO2 < 22 mL/kg/min), and severe HF (HF2) (n = 9, VO2 ≤ 14 mL/kg/min). Results: Based on the statistical analysis with 20-100% restriction, FDR correction (p-value 0.05) and 2.0-fold change across the three time points (TP1, TP2, TP3) criteria, we obtained 11 differentially expressed genes (DEG). Out of these 11 genes, the median Gene Expression Profile value decreased from TP1 to TP2 in 10 genes. The only gene that did not follow this pattern was CCDC181. By performing 1-way ANOVA, we identified 8/11 genes in each of the two groups (HV versus HF) while 5 of the genes (TTC34, TMEM119, C19orf33, ID1, TKTL2) overlapped between the two groups. We found 265 genes which are differentially expressed between those who survived and those who died. Conclusions: From our proof-of-concept heart failure study, we conclude that gene expression correlates with VO2 peak in both healthy individuals and HF patients, potentially by regulating various physiological processes involved in oxygen uptake and utilization during exercise. Multi-omics profiling may help identify novel biomarkers for assessing exercise capacity and prognosis in HF patients, as well as potential targets for therapeutic intervention to improve VO2 peak and quality of life. We anticipate that our results will provide a novel metric for classifying immune health.
RESUMO
BACKGROUND: Over the last decade, expanding use of molecular diagnostics in heart transplantation has allowed implementation of non-invasive surveillance strategies for monitoring allograft health. The commercially available HeartCare platform combines the AlloMap gene expression profiling assay and the AlloSure donor-derived cell-free DNA test (dd-cfDNA). Beyond their established use for assessment of rejection, evidence is building for predictive utility, with the longitudinal AlloMap Variability score previously shown to correlate with the risk of future rejection, graft dysfunction, re-transplantation, or death. In this single-center, retrospective pilot study, we evaluated the performance of a novel AlloSure Variability metric in predicting mortality in a cohort of heart transplant recipients. METHODS: Seventy-two adult heart transplant recipients with at least 3 concurrent AlloMap/AlloSure results were included. Demographic, clinical, imaging, and laboratory parameters were captured. Variability was defined as the standard deviation of longitudinal AlloMap/AlloSure results. A Cox multivariable adjusted proportional hazards model was used to evaluate the variability metrics as predictors of mortality. Associations between AlloMap/AlloSure variability and donor specific antibody (DSA) status were also assessed. RESULTS: A total of 5 patients (6.9%) died during a median follow-up of 480 days. In a univariate Cox proportional hazards model, higher AlloSure variability (HR 1.66, 95%CI 1.14 - 2.41), but not AlloMap variability or the cross-sectional AlloSure/AlloMap results was associated with increased mortality risk. Longitudinal AlloSure variability was also higher among patients with both preformed DSA and those developing de novo DSA. CONCLUSION: Our results suggest that increased variability of dd-cfDNA in heart transplant patients is associated with both mortality risk and the presence of donor specific antibodies. These findings highlight the added value of longitudinal data in the interpretation of AlloMap/AlloSure scores in this population and open the door to larger studies investigating the utility of these metrics in shaping post-transplant clinical care paradigms.
