Abstract Body: Introduction: Patients with sickle cell anemia (SCA) have cardiomyopathy leading to sudden cardiac death and ventricular arrhythmias. We previously reported that transgenic SCA mouse hearts exhibit systemic inflammation and interleukin-18 (IL-18) mediated inflammasome signaling, causing prolongation of action potential duration (APD) and ventricular tachyarrhythmias (VT). R-propranolol (R-P), an enantiomer of β-blocker L-propranolol, may prevent VT in SCA mice through a β-independent pathway via activation of the sterol regulatory binding protein (SREBP1). Ca²⁺ handling is a potential target of R-P to reduce cardiac arrhythmias via SREBP1 activation.

Goal: To establish the mechanisms behind the R-P induced reduction of ventricular arrhythmias in SCA mouse hearts.

Methods: Prior to recording, mice were treated with R-P (3 or 12.5 mg/kg, IP, 14 days). We optically mapped Langendorff perfused hearts from homozygous Townes SCA mice or non-sickling controls (CTR) at baseline and after perfusion of 5 ng/ml IL- 18 (60 min). Isolated ventricular myocytes from SCA mouse hearts were used for patch clamp and Ca²⁺ imaging.

Results: Untreated SCA mouse ventricular cardiomyocytes showed a leftward shift in Cav1.2 channel current activation curves (V_{1/2 max} = -28 ± 2 mV, SCA vs. -19 ± 1 mV, CTR), which is known to induce early after depolarizations and premature ventricular contractions (PVCs). IL-18 perfusion (60 min) induced PVCs in 2 of 8 (25%) R-P treated SCA mouse hearts relative to vehicle treated SCA mouse hearts (4 of 4). Western blot analysis revealed a significant reduction of Cav1.2 channel protein levels in vehicle treated SCA mouse LV and R-P increased SCA mouse LV Cav1.2 protein levels relative to vehicle. Ca²⁺ transient amplitudes were increased in SCA mouse ventricular cardiomyocytes (Figure 1A) and reduced to control levels with R-P (Figure 1B).

Conclusion: R-P normalization of aberrant Ca²⁺ handling, which may explain the antiarrhythmic potential of R-P in SCA mice, supports a role for R-P as a potential therapeutic for SCA patients.