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00925njm 22002777a 4500 dc Abdellatif, Mahmoud author Trummer-Herbst, Viktoria author Koser, Franziska author Durand, Sylvère author Adão, Rui author Vasques-Nóvoa, Francisco author Freundt, Johanna K author Voglhuber, Julia author Pricolo, Maria-Rosaria author Kasa, Michael author Türk, Clara author Aprahamian, Fanny author Herrero-Galán, Elías author Hofer, Sebastian J author Pendl, Tobias author Rech, Lavinia author Kargl, Julia author Anto-Michel, Nathaly author Ljubojevic-Holzer, Senka author Schipke, Julia author Brandenberger, Christina author Auer, Martina author Schreiber, Renate author Koyani, Chintan N author Heinemann, Akos author Zirlik, Andreas author Schmidt, Albrecht author von Lewinski, Dirk author Scherr, Daniel author Rainer, Peter P author von Maltzahn, Julia author Mühlfeld, Christian author Krüger, Marcus author Frank, Saša author Madeo, Frank author Eisenberg, Tobias author Prokesch, Andreas author Leite-Moreira, Adelino F author Lourenço, André P author Alegre-Cebollada, Jorge author Kiechl, Stefan author Linke, Wolfgang A author Kroemer, Guido author Sedej, Simon author 2021 Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans. Sci Transl Med . 2021 Feb 10;13(580):eabd7064 10.1126/scitranslmed.abd7064 1946-6242 Science translational medicine 33568522 http://hdl.handle.net/20.500.12105/15164 Nicotinamide for the treatment of heart failure with preserved ejection fraction.