Propionic Acidemia-Induced Proarrhythmic Electrophysiological Alterations in Human iPSC-Derived Cardiomyocytes.

Area of Science:

• Cardiology
• Genetics
• Biochemistry

Background:

• Propionic acidemia (PA) is a metabolic disorder caused by propionyl-CoA carboxylase (PCC) deficiency, linked to cardiac issues like arrhythmias and sudden death.
• Understanding the cellular mechanisms of PA-induced cardiac electrical abnormalities is crucial for risk assessment and management.

Purpose of the Study:

• To investigate the effects of PCC deficiency on cardiomyocyte action potentials and ion currents.
• To elucidate the cellular basis of proarrhythmia in propionic acidemia.

Main Methods:

• Whole-cell patch-clamp electrophysiology was used on induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a PA patient and a healthy control.
• Action potentials and key ion currents (INa, INaL, ICaL, INCX) were recorded and analyzed.

Main Results:

• PCC deficiency prolonged action potential duration and induced delayed afterdepolarizations.
• Significant alterations in ion currents were observed, including reduced peak INa, increased INaL, decreased ICaL, and increased INCX.
• These changes occurred independently of overt cardiomyopathy.

Conclusions:

• PCC deficiency directly alters cardiomyocyte ion channel function, impacting cardiac excitability and calcium handling.
• These cellular electrophysiological changes contribute to the proarrhythmic risk associated with propionic acidemia.