Increased Ca²⁺ Transient Underlies RyR2-Related Left Ventricular Noncompaction

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• A loss-of-function mutation in cardiac ryanodine receptor 2 (RyR2), I4855M^+/-, is linked to RyR2 Ca²⁺ release deficiency syndrome (CRDS) and left ventricular noncompaction (LVNC).
• While the mechanism of CRDS is understood, the link between RyR2 loss-of-function and LVNC remains unclear.

Purpose of the Study:

• To investigate the impact of the CRDS-LVNC-associated RyR2-I4855M^+/- loss-of-function mutation on cardiac structure and function.
• To elucidate the molecular mechanisms by which this RyR2 mutation contributes to LVNC.

Main Methods:

• Generation of a mouse model harboring the RyR2-I4855M^+/- mutation.
• Characterization using histology, echocardiography, ECG, and intact heart Ca²⁺ imaging.
• Analysis of Ca²⁺ handling proteins and phosphorylation status.

Main Results:

• RyR2-I4855M^+/- mice exhibited LVNC with hypertrabeculation, similar to human patients.
• Mice showed increased susceptibility to electrical stimulation-induced arrhythmias but protection from stress-induced arrhythmias.
• The mutation increased peak Ca²⁺ transient (enhanced Ca²⁺-induced Ca²⁺ release gain), abolished Ca²⁺ leak, elevated sarcoplasmic reticulum Ca²⁺ load, and increased end-diastolic Ca²⁺ levels.
• Increased phosphorylated CaMKII was observed, without changes in total CaMKII or other key proteins.

Conclusions:

• RyR2-I4855M^+/- mice serve as the first animal model for RyR2-associated LVNC, mirroring the human CRDS-LVNC phenotype.
• The mutation enhances peak systolic Ca²⁺ and end-diastolic Ca²⁺ levels by increasing Ca²⁺ release gain and prolonging Ca²⁺ transient decay.
• Elevated peak-systolic and end-diastolic Ca²⁺ levels are suggested as the underlying cause of RyR2-associated LVNC.