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The role mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes in the heart. However, most EHT systems are unable to model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained fractional shortening of >10%. To do this, 3D EHTs are integrated with an elastic polydimethylsiloxane (PDMS) strip that provides mechanical pre- and afterload to the tissue in addition to enabling contractile force measurements based on strip bending. Our results demonstrate in wild-type EHTs that dynamic loading is beneficial based on the magnitude of the forces, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we use hiPSC–derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy (ACM) due to mutations in desmoplakin. We demonstrate that manifestation of this desmosome-linked disease state requires the dyn-EHT conditioning and that it cannot be induced using 2D or standard 3D EHT approaches. Thus, dynamic loading strategy is necessary to provoke a disease phenotype (diastolic lengthening, reduction of desmosome counts, and reduced contractility), which are akin to primary endpoints of clinical disease, such as chamber thinning and reduced cardiac output.Single Sentence SummaryDevelopment of a dynamic mechanical loading platform to improve contractile function of engineered heart tissues and study cardiac disease progression.

Background Maintenance of sinus rhythm is the primary therapeutic goal for symptomatic atrial fibrillation (AF) patients but remains difficult to achieve because of suboptimal treatment options. While being effective in detecting and terminating AF, the widespread use of implantable atrial defibrillators is limited due to patients intolerance to repeated shocks. The negative adverse effects of electroshock therapy can hypothetically be overcome by allowing the heart itself to produce the electric current required for arrhythmia termination. As a result, the effector function of an electrical defibrillator would be provided by the heart itself, and therefore no longer rely on electronics, but on bioelectricity instead. Purpose To develop a hybrid bio-electronic system for automated and acute shock-free AF treatment. Methods To equip the heart with the effector function of the envisioned AF termination system, adeno-associated virus (AAV) vectors encoding red-activatable channelrhodopsin (ReaChR) (n=12) or citrine (n=4) were delivered locally to the right atrium (RA) of adult Wistar rats by gene painting. Four to 8 weeks later, AF was induced in vivo by atrial burst pacing after carbachol administration, followed by programmed local illumination of the RA by an implanted intrathoracic LED device whose activation was automatically regulated by an electrocardiogram (ECG)-based cardiac rhythm monitor. Results Gene painting of the RA resulted in transmural transduction of right atrial myocytes (78±6%) with minimum transgene expression of the left atrium and ventricles (6±2% and Conclusions By using a hybrid bio-electronic approach to modulate cardiac excitability, our study delivers proof that AF can be detected and terminated automatically in a safe, effective and repetitive, yet shock-free manner. These findings may create the basis for the development of pain-free device therapy for cardiac arrhythmias, thereby paving the way for ambulatory AF treatment with the perspective to improve patients' prognosis and quality of life. Acknowledgement/Funding NWO Vidi grant (1714336) and ERC Starting Grant (716509) both to D.A.P.

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. We show that local, right atrial delivery of adenoassociated virus vectors encoding a light-gated depolarizing ion channel results in efficient and spatially confined transgene expression. Activation of an implanted intrathoracic light-emitting diode device allows for termination of AF by illuminating part of the atria. Combining this newly obtained antiarrhythmic effector function of the heart with the arrhythmia detector function of a machine-based cardiac rhythm monitor in the closed chest of adult rats allowed automated and rapid arrhythmia detection and termination in a safe, effective, repetitive, yet shock-free manner. These findings hold translational potential for the development of shock-free antiarrhythmic device therapy for ambulatory treatment of AF.

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.