Background/Objectives: The cardiac hypoxia- and inflammation-associated processes in patients with chronic coronary artery disease remain unknown. The coronary sinus (CS) can be used to explore changes in cardiac microenvironment. This study sought to evaluate acute changes in the CS concentration of hypoxia and inflammation-associated biomarkers after the percutaneous revascularization of chronic total occlusions (CTO-PCI). Additionally, we explored changes in systemic inflammation and the potential of CS biomarkers to predict left ventricular ejection fraction (LVEF) improvement on follow-up. Methods: Thirty-three patients undergoing CTO-PCI were included. Samples from CS were collected before and after the revascularization. Twenty-six protein biomarkers associated with hypoxia and inflammation were measured using proximity extension assay technology. Systemic inflammation markers and LVEF on cardiac magnetic resonance imaging were assessed at baseline and 6-month follow-up. Results: CTO-PCI yielded a significant decrease in the concentration of CS pro-angiogenic biomarkers (angiopoietin-1, vascular endothelial growth factors). In addition, there was a significant increase in the anti-inflammatory biomarker interleukin-10 and a decrease in several pro-inflammatory biomarkers like interleukin-1β. The acute response in cardiac microenvironment was followed by a mid-term reduction in systemic inflammatory markers, particularly high-sensitivity C-reactive protein. Notably, interleukin-10 showed good performance to identify patients achieving LVEF improvement on follow-up in our cohort. Conclusions: Our results suggest that CTO-PCI might attenuate cardiac hypoxic and inflammatory stress. These exploratory findings warrant confirmation in larger, controlled studies.

Background: Patients with heart failure and reduced ejection fraction (HFrEF) who achieve improved ejection fraction (HFimpEF) after guideline-directed medical therapy exhibit superior prognosis. However, functional impairment remains a hallmark of HF. Aims: To characterize and compare exercise capacity profiles via cardiopulmonary exercise testing (CPET) between patients with HFimpEF and those with persistently reduced ejection fraction (HFprEF) using a baseline-adjusted analysis. Methods: Data from a longitudinal cohort of 111 HFrEF patients with baseline and follow-up CPET data (minimum 6-month follow-up) were analyzed. Patients were stratified into HFimpEF and HFprEF groups, according to the Universal Definition of HF. Changes between groups were evaluated using Analysis of Covariance (ANCOVA) adjusted for baseline values, with non-parametric Bootstrapping (2000 resamples) and multiplicity. Results: We included 111 patients: 69 with HFimpEF (62.2%) and 42 with HFprEF (37.8%). At a median follow-up of 8.7 months, the HFimpEF group showed significantly greater reverse remodeling (adjusted ΔLVEF +19.9%, p < 0.001) and a greater reduction in NT-proBNP levels (−557.6 pg/mL, p = 0.042). Both groups demonstrated intra-group functional improvements. However, in adjusted between-group ANCOVA models, HFimpEF achieved a significantly greater recovery in percentage of predicted peak oxygen consumption (adjusted difference: +8.5%; 95% CI: 1.2 to 16.1; p = 0.021). Net adjusted between-group differences for absolute VO₂peak gain, submaximal threshold, ventilatory efficiency and recovery kinetics did not reach statistical significance. Multivariate analysis identified older age (beta −0.261, p = 0.010), diabetes mellitus (beta −0.210, p = 0.023) and baseline VO₂peak (beta −0.569, p < 0.001) as negative predictors of improvement. Conclusions: Comprehensive HFrEF management improves exercise capacity across all patients. Although HFimpEF yields superior gains in normalized aerobic capacity, overall functional trajectories are largely comparable between phenotypes. This structural-functional decoupling underscores persistent residual limitations in HFimpEF, supporting CPET for longitudinal risk stratification.