Suppression of Arrhythmia by Enhancing Mitochondrial Ca²⁺ Uptake in Catecholaminergic Ventricular Tachycardia Models

Area of Science:

• Cardiovascular Physiology
• Mitochondrial Biology
• Pharmacology

Background:

• Arrhythmias are a major cause of cardiovascular death, with limited treatment options due to antiarrhythmic drug side effects.
• Cardiomyocyte calcium (Ca²⁺) handling is critical for cardiac rhythm, and its dysregulation is linked to heart disease.
• Mitochondria play a key role in regulating intracellular Ca²⁺, making them potential therapeutic targets.

Purpose of the Study:

• To investigate the potential of pharmacologically activating mitochondrial Ca²⁺ uptake for treating cardiac arrhythmias.
• To evaluate novel compounds that enhance mitochondrial Ca²⁺ uptake as antiarrhythmic agents.
• To assess therapeutic efficacy in models of catecholaminergic polymorphic ventricular tachycardia (CPVT).

Main Methods:

• Tested efsevin, a voltage-dependent anion channel 2 (VDAC2) agonist, and kaempferol, a mitochondrial calcium uniporter (MCU) activator, in murine models of CPVT.
• Utilized in vitro and in vivo approaches, including isolated cardiomyocytes from RyR2^R4496C/WT mice and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
• Assessed the impact of compounds on Ca²⁺ waves, spontaneous action potentials, and stress-induced ventricular tachycardia.

Main Results:

• Efsevin prevented arrhythmogenic Ca²⁺ events and spontaneous action potentials in mouse cardiomyocytes.
• The antiarrhythmic effects of efsevin were dependent on mitochondrial Ca²⁺ uptake via the MCU.
• Both efsevin and kaempferol significantly reduced ventricular tachycardia episodes in vivo and abolished diastolic Ca²⁺ events in human iPSC-CMs.

Conclusions:

• Pharmacological enhancement of mitochondrial Ca²⁺ uptake (MiCUps) represents a promising therapeutic strategy for arrhythmias.
• Targeting mitochondrial Ca²⁺ transport offers a safer alternative to conventional antiarrhythmic drugs.
• Compounds activating mitochondrial Ca²⁺ uptake show potential for treating genetic and acquired cardiac arrhythmias.