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Hypertension affects 1 in 2 adults in the United States and is the leading risk factor for myocardial infarction and chronic kidney disease. While animal models have advanced our understanding of the effects of hypertension on the heart, molecular insight from human cardiovascular tissues is currently lacking. Building upon previous work describing a protocol for the systematic dissection and preservation of whole postmortem human hearts, we performed pilot multiomics analyses of postmortem human hearts from donors with (n = 3) and without (n = 2) hypertension. Using bulk RNA-seq, we identified a higher abundance of transcripts associated with DNA helicase activity, NAD-dependent deacetylase activity, and branched chain amino acid metabolism in hypertension compared to normotension. Using single-nucleus RNA-seq, we identified a loss of contractile vascular smooth muscle cells and greater endothelial cell proliferation associated with hypertension. Lastly, metabolomics revealed an abundance of metabolites upstream of NAD-dependent metabolic steps in fatty acid oxidation and the Krebs cycle, consistent with reductive stress, and a likely funneling of glycolytic intermediates into the pentose phosphate pathway. Together, these methods demonstrate a powerful technique for the investigation of human cardiovascular disease and lend insight into the molecular signature of hypertension in adult cardiac tissue.