Aims Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events.We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). Methods and results Baseline serum was quantitatively profiled for 42 known biologically relevant amine-based metabolites among 402 patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) Study (derivation group) and 240 patients from the Genetic Risk Assessment of Defibrillator Events (GRADE) Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. Three amines, N-methyl-Lhistidine, symmetric dimethylarginine (SDMA), and L-kynurenine, were derived and validated to be associated with all-cause mortality. The hazard ratios of mortality in PROSE-ICD and GRADE were 1.48 (95% confidence interval 1.14-1.92) and 1.67 (1.22-2.27) for N-methyl-L-histidine, 1.49 (1.17-1.91) and 1.77 (1.27-2.45) for SDMA, 1.31 (1.06-1.63) and 1.73 (1.32-2.27) for L-kynurenine, respectively. L-Histidine, SDMA, and L-kynurenine were associated with ventricular arrhythmia-induced ICD shocks in PROSE-ICD, but they did not reach statistical significance in the GRADE cohort. Conclusion Utilizing metabolic profiling in two independent prospective cohorts of patients undergoing ICD implantation for primary prevention of SCD, we identified several novel amine markers that were associated with appropriate shock and mortality. These findings shed insight into the potential biologic pathways leading to adverse events in ICD patients. Further studies are needed to confirm the prognostic value of these findings.
Bibliographical noteFunding Information:
This work was supported by the Donald W. Reynolds Foundation, and the National Institutes of Health (R01 HL091062 to G.F.T., R01 HL103946 to A.C., and R01 HL077398 to B.L.)
- Implantable cardioverter-defibrillator
- Ventricular arrhythmia