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American Heart Association

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Final ID: Mo085

Direct effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiomyocyte function as a potential therapy for Phospholamban cardiomyopathy

Abstract Body: Introduction: Phospholamban (PLN) cardiomyopathy is a dilated and arrhythmogenic cardiomyopathy caused by a single deletion of arginine in PLN gene (PLN-R14del). Clinically, It presents with heart failure, ventricular arrhythmias and sudden cardiac death, and there is still no effective and/or specific treatment besides the heart transplant.
Hypothesis: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular outcomes improvement in general heart failure patients in multiple clinical trials. We hypothesize that SGLT2 inhibitors could ameliorate the contractile dysfunction in PLN cardiomyopathy.
Goals: Identify whether there is a direct cardiac effect of SGLT2 inhibitors on PLN cardiomyopathy.
Approach: We used a human iPSC-derived cardiomyocyte (hiPSC-CMs) model of PLN cardiomyopathy that mimics the impaired contractility of the disease to evaluate the contractile function after 4 days of Empagliflozin treatment by using functional cellular imaging assays. Additionally, we evaluated the effect of Empagliflozin treatment on CaMKII phosphorylation and activation of apoptosis mediators by measuring protein expression. All the experiments were compared to results using a CRISPR-engineered isogenic (healthy) line control hiPSC-CMs.
Results: 4 days of Empagliflozin treatment significantly restored contractile function, decreased levels of CaMKII phosphorylation, and decreased apoptotic activity in hiPSC-CMs with PLN cardiomyopathy when compared to their healthy (isogenic) control.
Conclusions: Our study provided evidence that SGLT2 inhibitors might serve as a therapeutic strategy to ameliorate contractile dysfunction and suppress arrhythmia in PLN cardiomyopathy.
  • Hnatiuk, Anna  ( Stanford University , Palo Alto , California , United States )
  • Li, Alexander  ( Cardiovascular Institute, Stanford University , Palo Alto , California , United States )
  • Staudt, David  ( Stanford Childrens Health , Palo Alto , California , United States )
  • Serrano, Ricardo  ( Stanford University , Palo Alto , California , United States )
  • Mercola, Mark  ( STANFORD UNIVERSITY , Stanford , California , United States )
  • Author Disclosures:
    Anna Hnatiuk: DO NOT have relevant financial relationships | Alexander Li: DO NOT have relevant financial relationships | David Staudt: DO NOT have relevant financial relationships | Ricardo Serrano: No Answer | Mark Mercola: DO have relevant financial relationships ; Ownership Interest:Regencor, Inc.:Active (exists now) ; Consultant:Cytokinetics:Active (exists now) ; Individual Stocks/Stock Options:Vala Sciences:Active (exists now)
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception I

Monday, 07/22/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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