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Background Ventricular tachyarrhythmias (VTA) with low and varying signal amplitudes and morphologies may not be successfully identified utilizing traditional implantable cardioverter defibrillator algorithms. Objective Develop and validate a novel algorithm (VF Therapy Assurance, VFTA) to improve detection and timely delivery of high voltage therapy (HVT) for these arrhythmias. Method Arrhythmia detection was simulated on recorded VTA electrograms (EGMs) utilizing Abbott's Merlin.net database. EGMs where an HVT occurred only when VFTA was enabled, or where VFTA provided an HVT >30 seconds earlier than without VFTA were re-adjudicated with physician review. As VFTA never prevents detection or therapy, EGMs where VFTA didn't activate or alter HVT were not adjudicated. Results Among 564,353 recorded VTA EGMs from 20,000 devices, VFTA altered HVT in 105 EGMs from 67 devices. Physician adjudication determined that 81.9% (86/105) of these EGMs were true undertreated VTA episodes and would have received appropriate HVT with VFTA enabled. Furthermore, 65% (56/86) of the episodes were ventricular fibrillation, polymorphic, did not self-terminate during the recording window, or not amenable anti-tachycardia pacing. 87.5% (49/56) would not have elicited HVT without VFTA. Overall, VFTA provided new or earlier appropriate HVT in 0.27% (53/20,000) of devices with an increase in inappropriate HVT in 0.07% (14/20,000) devices. Conclusion The VFTA algorithm successfully identifies VTA missed by traditional detection algorithms, due to undersensed ventricular signals resulting in rate falling below the programmed detection rate. The use of VFTA increases the likelihood of delivering life-saving HVT.

Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of β-adrenergic (β-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that β-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest β-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.

Neuromodulation devices have been approved for the treatment of epilepsy and seizures, with many other applications currently under research investigation. These devices rely on implanted battery powered pulse generators, that require replacement over time. Miniaturized ultrasound powered implantable devices have the potential to eliminate the need for batteries in neuromodulation devices. While these devices have been assessed in vitro, long-term in vivo assessment is required to determine device safety and performance. In this study, we developed a multi-stage long-term test platform to assess the performance of miniaturized ultrasound powered implantable devices.

Translation of novel therapies from bench to bedside is hampered by profound disparities between animal and human genetics and physiology. The ability to test for efficacy and cardiotoxicity in a clinically relevant human model system would enable more rapid therapy development. We have developed a preclinical platform for validation of new therapies in human heart tissue using organotypic slices isolated from donor and end-stage failing hearts. A major advantage of the slices when compared with human iPS-derived cardiomyocytes is that native tissue architecture and extracellular matrix are preserved, thereby allowing investigation of multi-cellular physiology in normal or diseased myocardium. To validate this model, we used optical mapping of transmembrane potential and calcium transients. We found that normal human electrophysiology is preserved in slice preparations when compared with intact hearts, including slices obtained from the region of the sinus node. Physiology is maintained in slices during culture, enabling testing the acute and chronic effects of pharmacological, gene, cell, optogenetic, device and other therapies. This methodology offers a powerful high-throughput platform for assessing the physiological response of the human heart to disease and novel putative therapies.

Cardiovascular research has made a major contribution to an unprecedented 10 year increase in life expectancy during the last 50 years: most of this increase due to a decline in mortality from heart disease and stroke. The majority of the basic cardiovascular science discoveries, which have led to this impressive extension of human life, came from investigations conducted in various small and large animal models, ranging from mouse to pig. The small animal models are currently popular because they are amenable to genetic engineering and are relatively inexpensive. The large animal models are favored at the translational stage of the investigation, as they are anatomically and physiologically more proximal to humans, and can be implanted with various devices; however, they are expensive and less amenable to genetic manipulations. With the advent of CRISPR genetic engineering technology and the advances in implantable bioelectronics, the large animal models will continue to advance. The rabbit model is particularly poised to become one of the most popular among the animal models that recapitulate human heart diseases. Here we review an array of the rabbit models of atrial and ventricular arrhythmias, as well as a range of the imaging and device technologies enabling these investigations.

Background— Arrhythmia is the major cause of death in patients with heart failure, for which β-adrenergic receptor blockers are a mainstay therapy. But the role of β-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles. Methods and Results— We used optical imaging of action potentials and [Ca 2+ ] i transients to compare the β 1 - and β 2 -adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β 1 -Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca 2+ ] i transients duration (CaD) in donor but not in failing hearts, because of desensitization of β 1 -adrenergic receptor in heart failure. In contrast, β 2 -stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β 2 -Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca 2+ ] i transients duration. Both β 1 - and β 2 -stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β 1 - and β 2 -stimulation enhanced Purkinje fiber automaticity, whereas only β 2 -stimulation promoted Ca-mediated premature ventricular contractions in heart failure. Conclusions— During end-stage heart failure, β 2 -stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β 2 -Stimulation is, therefore, more arrhythmogenic than β 1 -stimulation. In particular, β 2 -stimulation increases the transmural difference between [Ca 2+ ] i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.

In order to study the applicability of the Fiber Reinforced Plastic (FRP) composite materials for light structure, a tensile compression test of a large number of FRP samples was carried out. Through statistically analysis of test data, we get the FRP's basic mechanical parameters like tensile strength, elongation, elastic modulus and we get the stress-strain curves. Compared with steel material properties, the tensile strength of the FRP is close to steel, but the elastic modulus is lower than steel's elastic modulus.

Rationale: β-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca 2+ overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. Objective: To determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. Methods and Results: Simultaneous optical mapping of transmembrane potential and Ca 2+ transients was performed in normal rabbit hearts during subepicardial injections (50 μL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30–60 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125–250 μmol/L], 1.33±1.46 PVCs per injection; P 2+ delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase inhibition or reduced perfusate [Ca 2+ ], which indicates a Ca 2+ -mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P P 2+ -induced PVCs. Conclusions: These data provide the first experimental demonstration that localized β-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca 2+ overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.

A long-sought, and thus far elusive, goal has been to develop drugs to manage diseases of excitability. One such disease that affects millions each year is cardiac arrhythmia, which occurs when electrical impulses in the heart become disordered, sometimes causing sudden death. Pharmacological management of cardiac arrhythmia has failed because it is not possible to predict how drugs that target cardiac ion channels, and have intrinsically complex dynamic interactions with ion channels, will alter the emergent electrical behavior generated in the heart. Here, we applied a computational model, which was informed and validated by experimental data, that defined key measurable parameters necessary to simulate the interaction kinetics of the anti-arrhythmic drugs flecainide and lidocaine with cardiac sodium channels. We then used the model to predict the effects of these drugs on normal human ventricular cellular and tissue electrical activity in the setting of a common arrhythmia trigger, spontaneous ventricular ectopy. The model forecasts the clinically relevant concentrations at which flecainide and lidocaine exacerbate, rather than ameliorate, arrhythmia. Experiments in rabbit hearts and simulations in human ventricles based on magnetic resonance images validated the model predictions. This computational framework initiates the first steps toward development of a virtual drug-screening system that models drug-channel interactions and predicts the effects of drugs on emergent electrical activity in the heart.