PFKFB2 Gates a Relationship Between Cardiac Glycolytic Regulation and Electrophysiological Function

Area of Science:

• Cardiovascular Physiology
• Metabolic Regulation
• Cardiac Electrophysiology

Background:

• Metabolic heart diseases are linked to increased risks of arrhythmia and sudden cardiac death.
• Impaired insulin signaling, a hallmark of metabolic heart disease, leads to degradation of cardiac phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2), a key glycolytic regulator.
• The potential link between glycolytic dysregulation and cardiac electrophysiological dysfunction remains unclear.

Purpose of the Study:

• To investigate the impact of PFKFB2 loss on cardiac electrophysiology.
• To determine if PFKFB2 deficiency is sufficient to cause cardiac arrhythmias.
• To explore PFKFB2 as a potential therapeutic target for metabolic heart disease.

Main Methods:

• Utilized a cardiomyocyte-specific PFKFB2 knockout mouse model (cKO) and litter-matched controls (CON).
• Performed electrocardiography under fed and fasted states, at baseline, and during acute stress.
• Conducted patch-clamp electrophysiology and IonOptix Ca2+ transient measurements in isolated ventricular cardiomyocytes.

Main Results:

• cKO mouse hearts showed prolonged repolarization (QT interval, action potential duration).
• Impaired Ca2+ reuptake and increased spontaneous Ca2+ release were observed in cKO cardiomyocytes.
• Ventricular tachyarrhythmia occurred in cKO mice, exacerbated in the fed state.

Conclusions:

• Cardiac PFKFB2 loss is sufficient to induce electrophysiological instability and arrhythmias, particularly with adequate glucose availability.
• PFKFB2 is decreased in human hearts with heart failure with preserved ejection fraction.
• PFKFB2 stabilization presents a promising therapeutic strategy for enhancing electrophysiological stability in metabolic heart disease.