Preliminary findings on ultrasound modulation of the electromechanical function of human stem-cell-derived cardiomyocytes

It is estimated that one million cases of syncope and sudden cardiac death are caused by arrhythmias every year in the United States and Europe. We hypothesize that low-intensity non-ablative ultrasound (US) may offer an alternative to drug therapy and implantable defibrillators for modulation of cardiac electrophysiology. Previous studies and our own preliminary results have shown that cardiac pacing via ultrasound may be possible, however only limited sets of ultrasound parameters have been tested so far. Mechanosenitivity of cardiomyocytes (CMs) is well documented yet very few studies have pursued identification of the molecular correlates of cardiomyocyte response to ultrasound, and no mechanistic studies have been done before in human induced pluripotent stem cell-derived ventricular CMs (iPS-CMs). The aims of this project have been to find optimal ultrasound parameters to safely and effectively control cardiac electromechanical activity of human cardiomyocytes, including controlling reversible change in pacing rate, initiation and termination of activity and to study molecular mechanisms of cardiac electromechanical response to low-intensity ultrasound stimulation. Preliminary studies were performed on human iPS-CMs in a system for all-optical cardiac electrophysiology (OptoDyCE). This system allows for optical pacing of the cardiomyocytes as well as fluorescence imaging of intracellular calcium and membrane voltage. Combining the OptoDyCE system with a therapeutic ultrasound system is a novel method for probing ultrasound effects at the molecular level. Initial tests have shown that low intensity ultrasound may be able to facilitate pacing or rate modulation of cardiomyocytes, however further studies are needed to quantify the ultrasound effects at all desired parameters as well as probe the molecular mechanisms that facilitate these effects.