Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction

Chengyi Tu; Arianne Caudal; Yu Liu; Nikoloz Gorgodze; Hao Zhang; Chi Keung Lam; Yuqin Dai; Angela Zhang; Alexa Wnorowski; Matthew A Wu; Huaxiao Yang; Oscar J Abilez; Xuchao Lyu; Sanjiv M Narayan; Luisa Mestroni; Matthew R G Taylor; Fabio A Recchia; Joseph C Wu

doi:10.1038/s41551-023-01134-x

Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction

Nat Biomed Eng. 2023 Nov 27. doi: 10.1038/s41551-023-01134-x. Online ahead of print.

Authors

Chengyi Tu¹, Arianne Caudal¹, Yu Liu¹, Nikoloz Gorgodze², Hao Zhang¹, Chi Keung Lam¹, Yuqin Dai³, Angela Zhang^{1

4}, Alexa Wnorowski¹, Matthew A Wu^{1

4}, Huaxiao Yang¹, Oscar J Abilez¹, Xuchao Lyu⁵, Sanjiv M Narayan⁶, Luisa Mestroni^{7

8}, Matthew R G Taylor^{7

8}, Fabio A Recchia^{2

9

10}, Joseph C Wu^{11

12

13}

Affiliations

¹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
² Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
³ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Greenstone Biosciences, Palo Alto, CA, USA.
⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
⁶ Department of Medicine, Stanford University, Stanford, CA, USA.
⁷ Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA.
⁸ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA.
⁹ Scuola Superiore Sant'Anna, Pisa, Italy.
¹⁰ Institute of Clinical Physiology of the National Research Council, Pisa, Italy.
¹¹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. joewu@stanford.edu.
¹² Department of Medicine, Stanford University, Stanford, CA, USA. joewu@stanford.edu.
¹³ Department of Radiology, Stanford University, Stanford, CA, USA. joewu@stanford.edu.

PMID: 38012305
DOI: 10.1038/s41551-023-01134-x

Abstract

Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD⁺ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

Abstract

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