N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction

BACKGROUND: Patients with ischemic cardiomyopathy (ICM) have worse outcomes than those with coronary artery disease alone and those with non‐ICM. N8‐acetylspermidine (N8AS) is a polyamine that regulates ischemic cardiac apoptosis and resultant cardiac dysfunction. We hypothesized that N8AS is a mechanistic biomarker of adverse outcomes in patients with ICM. METHODS AND RESULTS: High‐resolution plasma metabolomics profiling and mass spectrometry were used to quantitate N8AS levels in a discovery cohort of 474 patients with coronary artery disease (age: 68±11 years, 12% black, 26% women): 154 with ICM, and 320 without ICM; and in an external validation cohort of 85 patients with ICM (age: 60±12 years, 37% black, 19% women). Patients without heart failure (HF) at baseline were followed for incident HF. The association between N8AS (log(2)‐transformed, standardized) and outcomes of all‐cause mortality and incident HF were examined using Cox regression. N8AS was higher (10.39 [interquartile range, 7.21–17.75] versus 8.29 nmol/L [interquartile range, 5.91–11.42]; P<0.001) in patients with ICM compared with patients who had coronary artery disease without ICM. Higher N8AS levels were associated with higher mortality in patients with ICM (hazard ratio [HR], 1.48; 95% CI, 1.19–1.85 per SD increase [P=0.001]), independent of B‐type natriuretic peptide, high‐sensitivity troponin I, and high‐sensitivity C‐reactive protein. Findings were validated in the independent cohort. Moreover, higher N8AS level was associated with incident HF in patients without HF at baseline (HR, 4.16; 95% CI, 1.41–12.25 per SD increase [P=0.01]). CONCLUSIONS: Independent of traditional HF measures, higher N8AS levels are associated with higher mortality in patients with ICM and incident HF in those who have coronary artery disease without HF. N8AS is a novel mechanistic biomarker in ICM.