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Current advances in single-cell proteomics and spatial multiomics by mass spectrometry imaging allow systematic dissection of clinically defined cardiovascular tissues with an unprecedented molecular resolving power, yet remain relatively underutilized in cardiovascular research. This compendium review works to stimulate new research into spatial regulation of the heart, emphasizing integration of single-cell proteomic regulation with comprehensive multiomic mass spectrometry imaging studies. In this context, we outline conceptual foundations, technological innovations, and biological insights that have resulted in the current success of single-cell proteomic and spatial multiomic analyses in cardiovascular disease. We provide an experimental design knowledge base of critical components in single-cell proteomics and spatial workflows by mass spectrometry imaging, essential for generating robust and reproducible data sets that are interpretable by advanced computational methods. 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