INTRODUCTION:Myocardial injury is a hallmark of heart failure (HF). It is unknown whether established (e.g. troponin) or novel biomarkers of myocardial injury [e.g. cardiac myosin-binding protein C (cMyBP-C)] provide additive diagnostic value beyond natriuretic peptides in community patients with suspected HF. METHODS:Community-based patients with suspected HF and elevated NT-proBNP levels were recruited into a multicentre, prospective, observational study at five sites (NCT04724200). Venous blood sampling was performed at the time of echocardiography. HF was classified according to left ventricular ejection fraction: HF with reduced ejection fraction (HFrEF) = ≤40%, HF with mildly reduced ejection (HFmrEF) = 41-49%, and HF with preserved ejection fraction (HFpEF) = ≥50% with HFA-PEFF score ≥5. NT-proBNP (Roche Elecsys® assay), high-sensitivity cardiac troponin T (hs-cTnT, Roche Elecsys® assay) and cMyBP-C (Roche precommercial assay) were measured. Diagnostic accuracy of each biomarker alone and in combination was examined using the area under the receiver operating characteristic curve (AUROC). RESULTS:Of 867 patients, 751 (87%) had measurable left ventricular ejection fraction and available biomarker data. Of these, 43 (6%) had HFrEF, 75 (10%) HFmrEF, and 278 (37%) HFpEF. NT-proBNP levels were highest in patients with HFrEF, with similar patterns observed for hsTnT and cMyBP-C. For the diagnosis of HF versus no HF, the combination of NT-proBNP and cMyBP-C had the highest AUROC of 0.77 (95%CI 0.73-0.80) versus NT-proBNP alone [0.74 (0.71-0.78); P = .003]. For detection of HFrEF versus no HF, the AUROC was 0.90 (0.86-0.95) for the combination of NT-proBNP and cMyBP-C compared with 0.85 (0.80-0.90) for NT-proBNP alone (P = .006). CONCLUSION:Measurement of cMyBP-C improved the diagnostic accuracy of NT-proBNP in community-based patients with suspected HF, with greatest additive value for identifying HFrEF, and may help in the prioritization of echocardiography.