An integrated signature of extracellular matrix proteins and a diastolic function imaging parameter predicts post-MI long-term outcomes

Front Cardiovasc Med. 2023 Apr 12:10:1123682. doi: 10.3389/fcvm.2023.1123682. eCollection 2023.

Abstract

Background: Patients suffering from acute myocardial infarction (AMI) are at risk of secondary outcomes including major adverse cardiovascular events (MACE) and heart failure (HF). Comprehensive molecular phenotyping and cardiac imaging during the post-discharge time window may provide cues for risk stratification for the outcomes.

Materials and methods: In a prospective AMI cohort in New Zealand (N = 464), we measured plasma proteins and lipids 30 days after hospital discharge and inferred a unified partial correlation network with echocardiographic variables and established clinical biomarkers (creatinine, c-reactive protein, cardiac troponin I and natriuretic peptides). Using a network-based data integration approach (iOmicsPASS+), we identified predictive signatures of long-term secondary outcomes based on plasma protein, lipid, imaging markers and clinical biomarkers and assessed the prognostic potential in an independent cohort from Singapore (N = 190).

Results: The post-discharge levels of plasma proteins and lipids showed strong correlations within each molecular type, reflecting concerted homeostatic regulation after primary MI events. However, the two molecular types were largely independent with distinct correlation structures with established prognostic imaging parameters and clinical biomarkers. To deal with massively correlated predictive features, we used iOmicsPASS + to identify subnetwork signatures of 211 and 189 data features (nodes) predictive of MACE and HF events, respectively (160 overlapping). The predictive features were primarily imaging parameters, including left ventricular and atrial parameters, tissue Doppler parameters, and proteins involved in extracellular matrix (ECM) organization, cell differentiation, chemotaxis, and inflammation. The network signatures contained plasma protein pairs with area-under-the-curve (AUC) values up to 0.74 for HF prediction in the validation cohort, but the pair of NT-proBNP and fibulin-3 (EFEMP1) was the best predictor (AUC = 0.80). This suggests that there were a handful of plasma proteins with mechanistic and functional roles in predisposing patients to the secondary outcomes, although they may be weaker prognostic markers than natriuretic peptides individually. Among those, the diastolic function parameter (E/e' - an indicator of left ventricular filling pressure) and two ECM proteins, EFEMP1 and follistatin-like 3 (FSTL3) showed comparable performance to NT-proBNP and outperformed left ventricular measures as benchmark prognostic factors for post-MI HF.

Conclusion: Post-discharge levels of E/e', EFEMP1 and FSTL3 are promising complementary markers of secondary adverse outcomes in AMI patients.

Keywords: echocardiogaphy; heart failure hospitalization; integrative analysis; major adverse cardiac events (MACE); multi-omics.

Grants and funding

This work was supported in part by grants from National Medical Research Council of Singapore (CIRG17may014 and MOH-000280 to MYC), from New Zealand: The Coronary Disease Cohort Study was funded by the Health Research Council of New Zealand (Program Grants 02/152, 08/070, 11/1070); National Heart Foundation of New Zealand; New Zealand Lotteries Grant Board; Foundation for Research, Science and Technology, and the Christchurch Heart Institute Trust, and National Medical Research Council of Singapore (to AMR). AMR holds the NZ Heart Foundation Chair of Cardiovascular Studies; the National University of Singapore via the Life Sciences Institute (LSI) (to MRW), National Research Foundation (NRFI2015-05, NRFSBP-P4 to MRW) and A*STAR (I1901E0040 to MRW); Singapore Ministry of Education (MOE2016/T2/1/001, NMRC/CG/M009/2017, MOE2018/T2/2/058, MOE-T2EP20121-0018 to HC). APP holds the Heart Foundation of New Zealand Foundation100 Fellowship. MYC receives salary support and research grant support from a clinician scientist award --senior investigator (NMRC MOH-000280-00), centre grant (NMRC CG21APR1008), Collaborative Centre Grant scheme (NMRC/CG21APRC006), MOH Health Services Research Program (MOH MH70:70/1-2017). MYC also received funding from an Externally Sponsored Clinical Research (ESCR) grant supported by Astra Zeneca but the funding has no involvement in the studies aforementioned in this article.