Incidence and clinical course of pacing-induced cardiomyopathy, predictive role of biomarkers of myocardial damage

Abstract Background/Introduction Pacing-induced cardiomyopathy (PICM) causes left ventricular dysfunction and heart failure, but its biological mechanisms remain unclear. Purpose To determine the incidence and clinical course of PICM in patients with preserved LV ejection fraction (LVEF) undergoing dual-chamber pacemaker implantation with expected high RV pacing burden, and to assess the predictive role of selected biomarkers of myocardial damage. Methods We prospectively enrolled consecutive adults with baseline LVEF 50% and atrioventricular block, receiving a first pacemaker with a right ventricular apical pacing lead. Inclusion required 85% ventricular pacing at a 3-week device interrogation. Baseline and 6-9 month follow-up clinical, device interrogation, echocardiographic data and eight biomarkers associated with myocardial injury or extracellular matrix homeostasis were collected. PICM was assessed, defined as a 10% reduction in LVEF with a resulting LVEF 50%. The optimal biomarker cut-off for predicting PICM was identified using the Youden index as well as an exhaustive assessment of all possible values with a conditional Poisson model. Results Seventy-eight patients were included, with a mean age of 75 years, and 67% of the population were male. The baseline LVEF was 63%. During a median follow-up of 8.6 months, 21 patients (26.9%) developed PICM. Patients with PICM faced higher rates of HF (47.6% vs 19.3%; p 0.019), and the composite endpoint of death, HF or cardiovascular readmission (61.9% vs 26.3%; p0.001). PICM was associated with a significant worsening of EuroQoL-5D scores. Among biomarkers, Matrix Metalloproteinase-1 (MMP-1) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) showed a non-linear association with the development of PICM. Low levels of these biomarkers appeared to be protective. The highest negative predictive value was obtained with cut-off values of 1.74 ng/mL for MMP-1 (NPV 85% for patients with lower levels), and 26.6 ng/mL for IGFBP7 (NPV 91%). In multivariate analysis, only older age independently predicted PICM (RR 1.43, p 0.001). Conclusion PICM is a frequent and relevant complication of RV apical pacing, occurring in over one quarter of patients with preserved LVEF. It confers a substantially increased risk of death, heart failure, and/or cardiovascular readmission. It is also associated with poorer quality of life. Selected biomarkers may reflect early extracellular matrix alterations that help us better understand why some individuals develop PICM while others do not. Biomarkers of extracellular matrix homeostasis could have a role in identifying patients at higher risk. This interaction could be mediated through TIMP-2 (Tissue Inhibitor of Metalloproteinases-2) that limits maladaptive fibrosis and ventricular remodelling. Improved risk stratification is essential to guide personalized pacing strategies and to make their implementation feasible across different implanting centres.