TY - JOUR
T1 - Nicotinamide forthe treatment of heart failure with preserved ejection fraction
AU - Abdellatif, Mahmoud
AU - Trummer-Herbst, Viktoria
AU - Koser, Franziska
AU - Durand, Sylvère
AU - Adão, Rui
AU - Francisco Vasques-Nóvoa, Vasques-Nóvoa
AU - Freundt, Johanna K.
AU - Voglhuber, Julia
AU - Pricolo, Maria Rosaria
AU - Kasa, Michael
AU - Türk, Clara
AU - Aprahamian, Fanny
AU - Herrero-Galán, Elías
AU - Hofer, Sebastian J.
AU - Pendl, Tobias
AU - Rech, Lavinia
AU - Kargl, Julia
AU - Anto-Michel, Nathaly
AU - Ljubojevic-Holzer, Senka
AU - Schipke, Julia
AU - Brandenberger, Christina
AU - Auer, Martina
AU - Schreiber, Renate
AU - Koyani, Chintan N.
AU - Heinemann, Akos
AU - Zirlik, Andreas
AU - Schmidt, Albrecht
AU - Von Lewinski, Dirk
AU - Scherr, Daniel
AU - Rainer, Peter P.
AU - Von Maltzahn, Julia
AU - Mühlfeld, Christian
AU - Krüger, Marcus
AU - Frank, Saša
AU - Madeo, Frank
AU - Eisenberg, Tobias
AU - Prokesch, Andreas
AU - Leite-Moreira, Adelino F.
AU - Lourenço, André P.
AU - Alegre-Cebollada, Jorge
AU - Kiechl, Stefan
AU - Linke, Wolfgang A.
AU - Kroemer, Guido
AU - Sedej, Simon
N1 - Publisher Copyright:
Copyright © 2021 The Authors.
PY - 2021/2/10
Y1 - 2021/2/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85101386937&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abd7064
DO - 10.1126/scitranslmed.abd7064
M3 - Article
C2 - 33568522
AN - SCOPUS:85101386937
SN - 1946-6234
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 580
M1 - eabd7064
ER -