Mahmoud Abdellatif, Viktoria Trummer-Herbst, Franziska Koser, Sylvère Durand, Rui Adão,Francisco Vasques-Nóvoa, Johanna K. Freundt, Julia Voglhuber, Maria-Rosaria Pricolo, Michael Kasa, Clara Türk, Fanny Aprahamian, Elías Herrero-Galán, Sebastian J. Hofer, Tobias Pendl, Lavinia Rech, Julia Kargl, Nathaly Anto-Michel, Senka Ljubojevic-Holzer, Julia Schipke, Christina Brandenberger, Martina Auer, Renate Schreiber, Chintan N. Koyani, Akos Heinemann, Andreas Zirlik, Albrecht Schmidt, Dirk von Lewinski, Daniel Scherr, Peter P. Rainer, Julia von Maltzahn, Christian Mühlfeld, Marcus Krüger, Saša Frank, Frank Madeo, Tobias Eisenberg, Andreas Prokesch, Adelino F. Leite-Moreira, André P. Lourenço, Jorge Alegre-Cebollada, Stefan Kiechl, Wolfgang A. Linke, Guido Kroemer* and Simon Sedej*.

Abstract: 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.

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