Optical mapping is a powerful imaging technique widely adopted to measure membrane potential changes and intracellular Ca²⁺ variations in excitable tissues using voltage-sensitive dyes and Ca²⁺ indicators, respectively. This powerful tool has rapidly become indispensable in the field of cardiac electrophysiology for studying depolarization wave propagation, estimating the conduction velocity of electrical impulses, and measuring Ca²⁺ dynamics in cardiac cells and tissues. In addition, mapping these electrophysiological parameters is important for understanding cardiac arrhythmia mechanisms. In this review, we delve into the fundamentals of cardiac optical mapping technology and its applications when applied to hiPSC-derived cardiomyocytes and discuss related advantages and challenges. We also provide a detailed description of the processing and analysis of optical mapping data, which is a crucial step in the study of cardiac diseases and arrhythmia mechanisms for extracting and comparing relevant electrophysiological parameters.

The intricate brain–heart interaction, essential for physiological balance, is largely governed by the autonomic nervous system (ANS). This bidirectional communication, involving both the sympathetic and parasympathetic branches of the ANS, is critical for maintaining cardiac homeostasis. Dysregulation of the ANS is a significant factor in cardiovascular diseases. Beyond the ANS, higher brain functions, particularly through interoceptive prediction, contribute to this dynamic interplay. The Cav1.3 L-type calcium channel, expressed in both the central nervous system (CNS) and the heart, is crucial for this interaction. Cav1.3, a key regulator of cellular excitability, exhibits genetic variations that are linked to both neurological and cardiac disorders, highlighting its pivotal role in the brain–heart axis. This review aims to delve into the under-explored role of Cav1.3 in brain–heart interaction, specifically examining how it modulates ANS activity and, consequently, the cardiac function. This will illuminate its significant role in the broader context of brain–heart interactions.

Heart failure (HF) affects approximately 6.7 million Americans and rising. Despite multi-modality therapy, patient outcomes remain suboptimal. It has been recently shown that Cav1.3 L-type calcium channels are re-expressed in ischemic failing human ventricles, and the Cav1.3-C-terminus is cleaved and acts as a transcription factor. Here, we leveraged the Cav1.3-C-terminus's auto-enhancer properties as a novel therapy to restore ejection fraction (EF) in HF. HF was established in wild-type (WT) and Cav1.3-heterozygous-knockout (Cav1.3^+/-) mice 15-days post-ligation of the left-anterior-descending coronary artery (LAD). Treatment groups received adeno-associated-virus-serotype-9(AAV9)-Cav1.3-C-terminus or vehicle. Echocardiography, histology, biochemistry, patch-clamp, optical mapping, and RNA-seq were performed. At day 15 post-LAD-ligation, WT-HF mice displayed fibrosis, impaired wall motion, increased left ventricular diameter in diastole and systole, and decreased left ventricular EF and fractional shortening vs. WT-Sham. Cav1.3 mRNA/protein levels increased in WT-HF mice vs. WT-Sham. At day 30 post-AAV9-Cav1.3-C-terminus-treatment, WT-Sham and Cav1.3^+/-HF mice showed increased L-type calcium current vs. vehicle. AAV9-Cav1.3-C-terminus-treated WT-HF mice returned to sinus rhythm after premature stimulation while vehicle-treated WT-HF mice showed arrhythmias such as bigeminy and triplets. Left ventricular EF normalized in both WT-HF and Cav1.3^+/-HF mice post-AAV9-Cav1.3-C-terminus-treatment. CACN1D, encoding Cav1.3, was upregulated 1.9-Log2-fold in the AAV9-Cav1.3-C-terminus-treated group vs. vehicle. AAV9-Cav1.3-C-terminus-treatment of mice with HF resulted in resistance to inducible arrhythmia and normalization of left ventricular EF, likely via a transcriptional upregulation of Cav1.3 and the resulting optimal increase in L-type calcium current. Therefore, AAV9-Cav1.3-C-terminus may be leveraged as a novel therapeutic approach to improve cardiac function.