Reversing the pipeline: a 'human-first' multi-omics approach to cardiovascular discovery

Despite significant biomedical advances, cardiovascular disease remains a leading cause of global mortality. The traditional 'bench-to-bedside' research pipeline, which heavily relies on animal models to guide clinical translation, is often hampered by species-specific physiological differences, leading to high rates of clinical trial failures. In this Review, we advocate for a paradigm shift toward a 'human-first' discovery approach. We explore how integrating human cardiac tissue resources obtained from biopsies, surgical explants and autopsies with high-resolution multi-omics technologies (including transcriptomics, proteomics and metabolomics) is transforming our understanding of complex heart diseases. We highlight recent breakthroughs in heart failure, ischemic heart disease, arrhythmias, myocarditis and valvular stenosis achieved through direct profiling of human samples. Finally, we propose a 'bedside-to-bench-and-back' strategy, in which therapeutic targets are identified in human tissues and then validated in animal models to accelerate the development of precise, clinically relevant cardiovascular treatments.