Next-generation molecular imaging of cardiac fibrosis

Cardiac fibrosis is a complex, dynamic pathophysiological process seen in virtually all forms of cardiovascular diseases. However, most current clinical definitions remain limited to static, anatomical constructs. Here we reconceptualise myocardial fibrosis as an active process, driven by transitions in fibroblast states, shaped by multicellular circuits and intrinsically embedded within a spatiotemporal matrix of extracellular remodelling. We present next-generation molecular imaging as a transformative platform to interrogate not only fibrotic burden but also the pathobiological mechanisms underlying disease. Leveraging insights from single-cell and spatial ‘omics, we describe a continuum of fibrotic phenotypes and introduce the concept of matreotypes: molecular fingerprints of extracellular matrix state and function. Advances in tracer development now allow in vivo mapping of key fibrotic mechanisms, including fibroblast activation, matrix proteolysis, collagen cross-linking, and epigenetic remodelling. We challenge the single-target paradigm and advocate for multiplex and activatable probes that capture complex disease biology. This approach integrates spatial, temporal, and systems-level biology to enable dynamic phenotyping and risk stratification. Finally, we propose a closed-loop framework combining imaging, ‘omics, and computational modelling to drive discovery with the aim to improve clinical decision-making, and precision cardiovascular care.