Proteomic Biomarkers Are Linked to QTc Interval in Patients With Chronic Heart Failure

Objective: This study investigates the link between circulating proteins and rate-corrected QT (QTc) interval in patients with heart failure with reduced ejection fraction (HFrEF) and their association with cardiovascular outcomes. Methods and Results: We analyzed 197 HFrEF patients from the prospective Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis (Bio-SHiFT) study, all in sinus rhythm at baseline. Baseline QTc intervals were calculated and corrected for broad QRS complexes (>120 ms) using Bogossian's formula. Using the Somalogic-SomaScan Assay, 1105 cardiovascular-related proteins were measured in baseline blood samples. Linear regression identified 11 biomarkers significantly associated with QTc interval (false discovery rate [FDR] < 0.05), adjusted for age, sex, and QT-prolonging medications. These included interleukin-1 receptor-like 1 (ST2) and angiopoietin-2. An additional four biomarkers showed potential relevance (FDR < 0.1). Cox regression analysis revealed that five biomarkers—ST2, angiopoietin-2, atrial natriuretic factor, insulin-like growth factor-binding protein 7 (IGFBP7), and carbonic anhydrase 4 (CA4)—were significantly associated with the composite clinical endpoint of cardiovascular death, heart transplantation, left ventricular assist device implantation, and heart failure hospitalization. Conclusion: Several cardiovascular proteins are associated with the QTc interval and adverse cardiovascular events in HFrEF patients. The observed associations highlight pathways such as inflammation, fibrosis, and angiogenesis, which may contribute to QTc prolongation and adverse outcomes in HFrEF. Further research is warranted to reveal underlying mechanisms and clinical applicability. Summary: This study is the first to investigate the association between QTc interval and a broad panel of over 1000 plasma proteins in patients with heart failure with reduced ejection fraction (HFrEF). We identified 11 proteins significantly linked to QTc interval, five of which also demonstrated prognostic relevance for adverse cardiovascular outcomes. The associated biomarkers are linked to inflammation, fibrosis, and angiogenesis-related pathways. These findings provide novel insights into the multifactorial mechanisms associated with QTc prolongation, potentially due to direct or indirect effects. The results emphasize the potential of circulating biomarkers as tools for understanding the pathophysiological processes associated with QTc prolongation and arrhythmogenesis in heart failure. Moreover, the identification of interleukin-1 receptor-like 1 (ST2), angiopoietin-2, atrial natriuretic factor, IGFBP7, and carbonic anhydrase 4 (CA4) as shared markers of QTc interval prolongation and adverse outcomes underscores their clinical utility as both diagnostic and prognostic biomarkers.