Caveolin-3 and Caveolae regulate ventricular repolarization.

RATIONALE: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. OBJECTIVE: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. METHODS AND RESULTS: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. CONCLUSION: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Robotic drill guide positioning using known-component 3D-2D image registration.

A method for x-ray image-guided robotic instrument positioning is reported and evaluated in preclinical studies of spinal pedicle screw placement with the aim of improving delivery of transpedicle K-wires and screws. The known-component (KC) registration algorithm was used to register the three-dimensional patient CT and drill guide surface model to intraoperative two-dimensional radiographs. Resulting transformations, combined with offline hand-eye calibration, drive the robotically held drill guide to target trajectories defined in the preoperative CT. The method was assessed in comparison with a more conventional tracker-based approach, and robustness to clinically realistic errors was tested in phantom and cadaver. Deviations from planned trajectories were analyzed in terms of target registration error (TRE) at the tooltip (mm) and approach angle (deg). In phantom studies, the KC approach resulted in [Formula: see text] and [Formula: see text], comparable with accuracy in tracker-based approach. In cadaver studies with realistic anatomical deformation, the KC approach yielded [Formula: see text] and [Formula: see text], with statistically significant improvement versus tracker ([Formula: see text] and [Formula: see text]). Robustness to deformation is attributed to relatively local rigidity of anatomy in radiographic views. X-ray guidance offered accurate robotic positioning and could fit naturally within clinical workflow of fluoroscopically guided procedures.