Serum amine-based metabolites and their association with outcomes in primary prevention implantable cardioverter-defibrillator patients.
OBJECTIVE
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).


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-l-histidine, 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.


CONCLUSIONS
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.
Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Yiyi
Y
Zhang
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 565, Baltimore, MD 21287, USA.
Elena
E
Blasco-Colmenares
Netherlands Metabolomics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Amy C
AC
Harms
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Barry
B
London
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Indrani
I
Halder
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Madhurmeet
M
Singh
Lifespan Cardiovascular Institute and the Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
Samuel C
SC
Dudley
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Rebecca
R
Gutmann
Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Eliseo
E
Guallar
Netherlands Metabolomics Centre, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.
Thomas
T
Hankemeier
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 565, Baltimore, MD 21287, USA.
Gordon F
GF
Tomaselli
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Halsted 565, Baltimore, MD 21287, USA alcheng@jhmi.edu.
Alan
A
Cheng
D000368:Aged; D000588:Amines / Q000097:blood*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D017147:Defibrillators, Implantable; D004554:Electric Countershock / Q000009:adverse effects / Q000295:instrumentation* / Q000401:mortality; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007737:Kynurenine / Q000097:blood; D008297:Male; D055432:Metabolomics; D008762:Methylhistidines / Q000097:blood; D008875:Middle Aged; D011237:Predictive Value of Tests; D011322:Primary Prevention / Q000379:methods*; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
D000588:Amines; D015415:Biomarkers; D008762:Methylhistidines; D007737:Kynurenine; C024917:symmetric dimethylarginine; D001120:Arginine
Amine; Implantable cardioverter-defibrillator; Metabolomics; Mortality; Ventricular arrhythmia