S100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure

Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.


Supplementary Table 1. Clinicopathological characteristics of patients with acute myocardial infarction (AMI) (n = 20) and healthy controls (HCs
Data were presented as absolute numbers (percentages) or medians (interquartile ranges).Categorical variables were analyzed using a two-sided χ² or Fisher's exact test.Continuous parametric data were analyzed using a two-sided t-test.Continuous non-parametric data were analyzed using a two-sided the Mann-Whitney U test.P < 0.05 was considered as significant.Source data are provided in the Source Data File.The new onset of signs and symptoms of HF were clinical manifestations such as dyspnea, orthopnea, peripheral edema, jugular vein dilatation, a third heart sound (S3), and lung rale.

Supplementary
worsening HF Killip class II progressed to III or IV, Killip class III progressed to IV cardiogenic shock systolic blood pressure ≤90 mm Hg for > 30 min after exclusion of hypovolaemia, with clinical evidence of hypoperfusion, inotrope dependence, or mechanical left ventricular support to correct the issue.

Death due to HF or cardiogenic shock
Death due to HF or cardiogenic shock was defined as a death with clinical, radiologic, or postmortem evidence of HF, in the absence of in-hospital acute ischemic events.

HF progression resulting in rehospitalization
A hospital readmission for which HF was the primary reason, specifically defined as an event meeting all of the following criteria: (1) admission to the hospital for at least 24 hours; (2) objective evidence of new or worsening HF (e.g., orthopnea, jugular venous distension, pulmonary basilar crackles, etc.); and (3) intensification of HF therapy (e.g., initiation of intravenous diuretics or inotropes).
Death due to HF Death due to HF was defined as death in the context of clinically worsening symptoms and/or signs of HF with no other apparent cause, death as a consequence of a surgical procedure to treat HF, or death after referral to hospice for HF.The patients were divided into subgroups that did or did not reach the primary endpoint of HF events.

Variables
The number of patients in each risk category was shown.The patients were divided into subgroups that did or did not reach the primary endpoint of HF events.
The number of patients in each risk category was shown.

Supplementary Table 6. Common differential proteins across the three groups 1 2 Protein abbreviation Full name of each protein AMI vs. HC HF events vs. No-HF events
-values were not corrected for multiple testing.Source data are provided in the Source Data File. P

Table 8 . C-statistics of clinical biomarkers and candidate proteins for HF events in the discovery cohort
BNP, B-type natriuretic peptide; CRP, C-reactive protein; cTnI, cardiac troponin I. Harrell's concordance C-statistic was used to compare the predictive accuracy of the candidate proteins and clinical biomarkers.All tests were two-sided and P < 0.05 was considered as significant.Source data are provided in the Source Data File.Supplementary Table9.

C-statistics of clinical biomarkers and candidate proteins for HF events in the validation cohort
-type natriuretic peptide; CRP, C-reactive protein; cTnI, cardiac troponin I. Harrell's concordance C-statistic was used to compare the predictive accuracy of the candidate proteins and clinical biomarkers.All tests were two-sided and P < 0.05 was considered as significant.

Table 14. 50 S100A9 cis-protein quantitative trait loci (pQTLs) and their association with S100A9 in the genome-wide association studies (GWAS) summary statistic
Data were presented as absolute numbers (percentages) or medians (interquartile ranges).Test for trend based on quartiles of S100A8/A9 levels.All tests were two-1 sided and P < 0.05 was considered as significant.Source data are provided in the Source Data File.Bold indicated P<0.05.