Mitochondria are crucial for cellular functioning, serving as both an intracellular energy source and a signaling organelle. Recent evidence also highlights their existence outside of cells, where they participate in cell-to-cell communication. Cardiometabolic disease (CMD) has a complex pathogenesis closely associated with mitochondrial dysregulation, inflammation, and metabolic abnormalities. This review explores the roles of circulating extracellular mitochondria (CEMI) in CMD, detailing how their various forms, whether as intact structures or within vesicles, contribute to CMD pathogenesis. We classify different forms of CEMIs and discuss their potential as biomarkers and therapeutic agents in CMDs. We also describe mitochondrial transplantation as an emerging therapy for restoring cellular function in damaged tissues. Finally, to standardize CEMI assessment, we propose the Universal CEMI Assessment Protocol (UCAP), a framework aimed at enhancing comparability and reproducibility across studies.

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR), with rarer forms occurring less frequently. AL amyloidosis arises from plasma cell-derived light chains and typically follows an aggressive clinical course, whereas ATTR amyloidosis results from misfolded wild-type or variant transthyretin and progresses more indolently. Extracellular vesicles (EVs) have recently been recognized as mediators of amyloid propagation, inflammation, and myocardial remodeling, particularly at later stages of disease. Despite growing evidence, no comprehensive reviews have focused on this relationship. We conducted a structured narrative review (PubMed and Scopus, 2020–2025) following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to synthesize emerging data. EVs act as scaffolds for transthyretin and serum amyloid A aggregation and carry disease-specific protein and RNA cargo detectable in blood and urine. Experimental models also demonstrate EV-mediated transport of serum amyloid A under conditions of cardiac stress, representing a reactive amyloidogenic pathway rather than a common cause of human cardiac amyloidosis. Preclinical studies show regenerative and anti-fibrotic effects of stem-cell-derived EVs, and early clinical trials demonstrate the feasibility of EV-based cardiac therapy. While methodological and translational challenges persist, EVs represent promising diagnostic and therapeutic tools that could transform the precision management of cardiac amyloidosis.