Associations between biomarkers and p-wave indices in relation to atrial fibrillation development in heart failure patients

Background The predictive value of atrial conduction abnormalities, reflected by P-wave indices (PWI), and their association with biomarkers signaling fibrosis for the development of atrial fibrillation (AF) in patients with heart failure (HF) remains underexplored. To address this gap, we investigated the associations between PWI, fibrotic biomarkers, and the risk of incident AF in a cohort of HF patients. Methods A total of 475 patients with new-onset or worsening HF, were followed for 5 years. Fibrosis-associated biomarkers (TIMP-2, MMP-2, MMP-3, MMP-9, ST-2, GDF-15, Gal-3) were analyzed using proximity extension assay. PWI (P-wave duration, P-wave amplitude in lead I, P-wave terminal force in V1, P-wave axis and P-wave morphology in inferior leads required for definition of interatrial block (IAB)) were derived from ECGs processed with the Glasgow algorithm. Cox regression assessed associations between the biomarkers, PWI, and incident AF. Results Among 475 individuals (mean age 74.6 years; 68% male), 41 developed incident AF over 5 years. Low P-wave amplitude at inclusion correlated negatively with GDF-15 (p < 0.001) and MMP-2 (p = 0.037) in both leads I and II. Six biomarkers were significantly associated with incident AF in adjusted analysis: TIMP-4 (HR 2.06, p=0.007), MMP-2 (HR 2.09, p=0.046), MMP-3 (HR 1.48, p=0.007), ST-2 (HR 1.66, p=0.003), GDF-15 (HR 2.26, p=0.001), and Gal-3 (HR 2.14, p=0.048). Among the PWI, P-wave axis <0° (HR: 4.74, p = 0.021) and low P-wave amplitude in lead I (HR: 2.09, p=0.036) were significantly associated with incident AF. Conclusions In this long-term prospective follow-up study of patients admitted for HF, biomarkers with proven associations to fibrosis were associated with incident AF. This study also showed that low P-wave amplitude may reflect abnormal LA-conduction pathway and displaced intra-atrial conduction pattern in advanced HF, as low P-wave in lead I and abnormal P-wave axis (<0 degree) were associated with incident AF.