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Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction

29 Pages Posted: 23 Mar 2022 Publication Status: Preprint

See all articles by Dennis Ding Hwa Wang

Dennis Ding Hwa Wang

University of Washington - Division of Cardiology

Sophia Airhart

University of Washington - Division of Cardiology

Bo Zhou

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine

Laura M. Shireman

University of Washington - School of Pharmacy

Siyi Jiang

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine

Carolina Melendez Rodriguez

University of Washington - Harborview Medical Center

James N. Kirkpatrick

University of Washington - Division of Cardiology

Danny Shen

University of Washington - School of Pharmacy

Rong Tian

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine

Kevin D. O'Brien

University of Washington - Division of Cardiology

Abstract

Objectives: Determine the safety and tolerability of the nicotinamide-adenine dinucleotide (NAD+) precursor, nicotinamide riboside (NR), and whether NR increases NR and NAD+ blood levels in participants with ACC/AHA Stage C heart failure with reduced ejection fraction (HFrEF).

Background: Mitochondrial dysfunction in heart failure is associated with alterations in intracellular levels of NAD+ and NADH. In mouse HFrEF models, NAD+ precursor supplementation blunts decline in cardiac function. No studies have examined the long-term safety and tolerability of NAD+ precursors in humans with Stage C HFrEF.

Methods: In a 12-week, randomized, placebo-controlled trial, 30 participants with Stage C HFrEF were randomized to either NR or matching placebo (2:1 allocation ratio). Participants were monitored for symptoms, laboratory values, blood NR/NAD+ levels, and exploratory endpoints. Mitochondrial respiratory function and inflammatory marker expression were assessed in participant peripheral blood mononuclear cells (PBMCs).

Results: There were no between-group differences in on-trial rates of adverse events or laboratory values. On-trial compliance was high, and the NR group had significantly higher blood NAD+ levels (NR: 30±20 vs. Placebo: -0.3±2 µmol, P<0.00001). There were no between-group differences in six-minute walk distance, LV function or quality of life score. In the NR group, relative NAD+ level increases correlated with increases in PBMC basal (R2=0.41, P=0.003) and maximal (R2=0.43, P=0.0022) respiration, and with decreased PBMC expression of the pro-inflammatory protein, NLRP3 (R2=0.33, P=0.02).

Conclusions: NR was safe, well-tolerated, and increased whole blood NAD+ levels. Relative blood NAD+ level increases correlated with improved mitochondrial function and decreased inflammatory marker expression in PBMCs.

Keywords: Nicotinamide Riboside, NAD, Heart Failure with Reduced Ejection Fraction, Sterile Inflammation, Mitochondrial Function

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Suggested Citation

Wang, Dennis Ding Hwa and Airhart, Sophia and Zhou, Bo and Shireman, Laura M. and Jiang, Siyi and Melendez Rodriguez, Carolina and Kirkpatrick, James N. and Shen, Danny and Tian, Rong and O'Brien, Kevin D., Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction. Available at SSRN: https://ssrn.com/abstract=4064493 or http://dx.doi.org/10.2139/ssrn.4064493

Dennis Ding Hwa Wang

University of Washington - Division of Cardiology ( email )

Seattle, WA
United States

Sophia Airhart

University of Washington - Division of Cardiology ( email )

Seattle, WA
United States

Bo Zhou

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine ( email )

Box 356340
1925 N.E. Pacific Street
Seattle, WA
United States

Laura M. Shireman

University of Washington - School of Pharmacy ( email )

Seattle, WA 98195
United States

Siyi Jiang

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine ( email )

Box 356340
1925 N.E. Pacific Street
Seattle, WA
United States

Carolina Melendez Rodriguez

University of Washington - Harborview Medical Center ( email )

WA
United States

James N. Kirkpatrick

University of Washington - Division of Cardiology ( email )

Seattle, WA
United States

Danny Shen

University of Washington - School of Pharmacy ( email )

Seattle, WA 98195
United States

Rong Tian

University of Washington, School of Medicine, Department of Anesthesiology and Pain Medicine ( email )

Box 356340
1925 N.E. Pacific Street
Seattle, WA
United States

Kevin D. O'Brien (Contact Author)

University of Washington - Division of Cardiology ( email )

Seattle, WA
United States

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