The Next Step: The Role of Metagenomic Next-Generation Sequencing in Microbial Detection of Culture-Negative Cardiovascular Infections

Cardiovascular infections, including those involving native and prosthetic heart valves, implantable cardiac devices, mechanical circulatory assist devices, and vascular grafts, are associated with significant morbidity and mortality risks. Optimal management of these complex infections requires pathogen-directed antimicrobial therapy. However, standard culture-based methods often fail to identify causative organisms due to prior antimicrobial use, infections due to fastidious organisms, or biofilm-associated infections. Emerging evidence suggests that microbial cell-free DNA (mcfDNA) and metagenomic testing can enhance pathogen detection, particularly in culture-negative cases. However, their results require careful clinical interpretation, often necessitating input from infectious diseases specialists. In this review, we examine published evidence regarding metagenomic testing for cardiovascular infections and its impact on patient care. We propose a framework for microbiological adjudication of mcfDNA results, introduce standardized definitions for clinical impact assessment, and provide guidance on integrating mcfDNA testing into diagnostic evaluation of patients with culture-negative cardiovascular infections.