# Tachycardia-induced Metabolic Remodeling Drives Cardiac Dysfunction

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $151,637

## Abstract

Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality.
Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases.
Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular
outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac
dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment,
especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in
induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular
signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr.
Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT).
In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To
validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure
will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the
disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia.
Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis
intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly,
promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based
on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect
the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will
employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis
intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This
K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr.
Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael
Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr.
Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers
(cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic
understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic
interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise,
providing substantial momentum to his transition toward...

## Key facts

- **NIH application ID:** 10906100
- **Project number:** 5K99HL164962-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Chengyi Tu
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $151,637
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-02-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906100

## Citation

> US National Institutes of Health, RePORTER application 10906100, Tachycardia-induced Metabolic Remodeling Drives Cardiac Dysfunction (5K99HL164962-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906100. Licensed CC0.

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