Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision...

Area of Science:

• Cardiology
• Genetics
• Electrophysiology

Background:

• Inherited phospholamban (PLN) R14del variants are linked to dilated cardiomyopathy and life-threatening ventricular arrhythmias.
• The precise single-cell electrophysiological mechanisms driving arrhythmogenicity in PLN R14del cardiomyopathy are not fully understood.
• The efficacy of existing antiarrhythmic drugs in this specific genetic context remains uncertain.

Purpose of the Study:

• To elucidate the genotype-specific electrophysiological phenotype of PLN R14del cardiomyocytes.
• To assess the impact of modulating ion currents on arrhythmic risk in PLN R14del models.
• To evaluate the responsiveness of PLN R14del cardiomyocytes to specific antiarrhythmic agents.

Main Methods:

• Utilized isogenic wild-type (WT) and CRISPR-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes.
• Employed high-throughput optical action potential recordings and a deep learning framework for AP morphology analysis.
• Tested the effects of a potassium current activator (NS-5806), a potassium current inhibitor (acacetin), and a late sodium current blocker (GS-967).

Main Results:

• PLN R14del cardiomyocytes displayed a proarrhythmic phenotype with reduced normal action potentials, prolonged duration, and increased early afterdepolarizations.
• The potassium channel activator NS-5806 exacerbated arrhythmias in PLN R14del cells, unlike in WT cells.
• The late sodium current blocker GS-967 also worsened arrhythmic features in the PLN R14del mutant line.

Conclusions:

• PLN R14del cardiomyopathy establishes a unique electrophysiological substrate that alters responses to antiarrhythmic drugs.
• Drugs effective in WT or other models may prove ineffective or proarrhythmic in PLN R14del patients.
• Genotype-specific, patient-derived iPSC models are crucial for preclinical antiarrhythmic drug evaluation and precision medicine in inherited cardiomyopathies.