Unbiased serum proteomics in heart failure and associated pulmonary hypertension: From biomarkers discovery to precision medicine

Heart failure (HF) and pulmonary hypertension (PH) due to left heart disease (PH-LHD) are complex and heterogeneous syndromes with diverse underlying mechanisms and variable clinical courses. Despite significant progress in clinical management, current diagnostic and prognostic approaches often fail to capture the underlying molecular diversity of these conditions. Unbiased serum proteomics offers a promising solution to enable novel biomarkers and pathophysiological pathways directly from patient samples. Using high-throughput mass spectrometry (MS) and aptamer-based platforms, proteomic profiling enables the simultaneous quantification of thousands of proteins across a wide dynamic range, offering a multidimensional perspective on disease mechanisms. In HF, proteomic signatures differentiate phenotypes such as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) through distinct inflammatory, metabolic and remodelling pathways, supporting more accurate diagnosis and risk assessment. In PH-LHD, dysregulated protein networks reflect pressure overload, atrial remodelling and right ventricular adaptation, supporting more refined phenotypic stratification. Integrating proteomic data with clinical, imaging and genomic variables enhances predictive accuracy and opens new avenues for individualized therapy. However, challenges remain, including pre-analytical variability, data interpretation and the need for rigorous validation across independent cohorts. This review discusses current advances in serum proteomics applied to HF and PH-LHD, methodological strengths and limitations and outlines the translational potential of proteomic findings to improve patient outcomes and support precision medicine.