Abstract-Optical techniques have revolutionized the investigation of cardiac cellular physiology and advanced our understanding of basic mechanisms of electrical activity, calcium homeostasis, and metabolism. Although optical methods are widely accepted and have been at the forefront of scientific discoveries, they have been primarily applied at cellular and subcellular levels and considerably less to whole heart organ physiology. Numerous technical difficulties had to be overcome to dynamically map physiological processes in intact hearts by optical methods. Problems of contraction artifacts, cellular heterogeneities, spatial and temporal resolution, limitations of surface images, depth-offield, and need for large fields of view (ranging from 2ϫ2 mm 2 to 3ϫ3 cm 2 ) have all led to the development of new devices and optical probes to monitor physiological parameters in intact hearts. This review aims to provide a critical overview of current approaches, their contributions to the field of cardiac electrophysiology, and future directions of various optical imaging modalities as applied to cardiac physiology at organ and tissue levels. Key Words: optical mapping Ⅲ fluorescent probes Ⅲ electrophysiology Ⅲ arrhythmia Ⅲ defibrillation M ammalian physiology has an ingrained hierarchy with molecular and cellular physiology at its base, followed by the interactions of large populations of cells and organ systems, and finally the integration of multiple organ functions of an entire animal. For the past 4 decades, cardiovascular physiology has been dominated by a "reductionist" approach, focusing on cellular mechanisms. Major strides have been accomplished in our understanding of cellular mechanisms, including metabolism, intracellular signaling, trafficking, ion channel structure, function, and expression. With a greater understanding of cellular mechanisms came the growing realization that organs such as the heart are composed of several types of interacting cells with significant and important heterogeneities of properties, cell-to-cell coupling, and function within each group. Thus, an understanding of molecular and cellular mechanisms must still be integrated to explain the more complex organ system while taking into account spatial and temporal heterogeneities of cell functions throughout the organ.Unfortunately, experimental methodologies available for studies at the organ level are not as abundant as at the cellular scale. Nonoptical imaging modalities, including positron emission tomography, magnetic resonance, and ultrasound imaging have only started to bridge molecular and organ physiology using novel contrast agents. 1 On the other hand, optical modes of imaging, in combination with parametersensitive probes have already demonstrated their ability to overcome the problem of spatiotemporal resolution in two dimensions for a wide range of applications from single molecular events to in vivo whole animal physiology.Fluorescence has been used to measure a wide range of physiological parameters in cells and tissues...

Background-There is an effort to build an anatomically and biophysically detailed virtual heart, and, although there are models for the atria and ventricles, there is no model for the sinoatrial node (SAN

Abstract-Although effects of shock strength and waveform on cardiac vulnerability to electric shocks have been extensively documented, the contribution of ventricular anatomy to shock-induced polarization and postshock propagation and thus, to shock outcome, has never been quantified; this is caused by lack of experimental methodology capable of mapping 3-D electrical activity. The goal of this study was to use optical imaging experiments and 3-D bidomain simulations to investigate the role of structural differences between left and right ventricles in vulnerability to electric shocks in rabbit hearts. The ventricles were paced apically, and uniform-field, truncated-exponential, monophasic shocks of reversed polarity were applied over a range of coupling intervals (CIs) in experiment and model. Experiments and simulations revealed that reversing the direction of externally-applied field (RVϪ or LVϪ shocks) alters the shape of the vulnerability area (VA), the 2-D grid encompassing episodes of arrhythmia induction. For RVϪ shocks, VA was nearly rectangular indicating little dependence of postshock arrhythmogenesis on CI. For LVϪ shocks, the probability of arrhythmia induction was higher for longer than for shorter CIs. The 3-D simulations demonstrated that these effects stem from the fact that reversal of field direction results in relocation of the main postshock excitable area from LV wall (RVϪ shocks) to septum (LVϪ shocks). Furthermore, the effect of septal (but not LV) excitable area in postshock propagation was found to strongly depend on preshock state. Knowledge regarding the location of the main postshock excitable area within the 3-D ventricular volume could be important for improving defibrillation efficacy. Key Words: ventricles Ⅲ virtual electrode polarization Ⅲ reentry Ⅲ excitable area Ⅲ arrhythmia induction D efibrillation and cardiac vulnerability to electric shocks are strongly linked. A large body of research has demonstrated that ventricular fibrillation induction with an electric shock in sinus rhythm and defibrillation are driven by the same mechanisms. 1-3 Furthermore, it has become a standard in the clinical practice of defibrillation to use the upper limit of vulnerability (ULV), which approximates the defibrillation threshold, 4 -8 in programming the implantable cardioverter/defibrillator. Therefore, complete understanding of the mechanisms by which a defibrillation shock fails in terminating lethal arrhythmias and subsequent optimization of the clinical procedure of defibrillation benefits from the knowledge regarding the factors that contribute to and alter cardiac vulnerability to electric shocks.Strength of the shock and its waveform are important factors affecting ventricular vulnerability to electric shocks. Equally important is the multifaceted ventricular structure with its convoluted geometry and complex fiber architecture. It provides a pathway through which the shock current flows; it also channels the propagation of the postshock activations. Whereas the effects of shock wavefo...

The rigidity and relatively primitive modes of operation of catheters equipped with sensing or actuation elements impede their conformal contact with soft-tissue surfaces, limit the scope of their uses, lengthen surgical times and increase the need for advanced surgical skills. Here, we report materials, device designs and fabrication approaches for integrating advanced electronic functionality with catheters for minimally invasive forms of cardiac surgery. By using multiphysics modelling, plastic heart models and Langendorff animal and human hearts, we show that soft electronic arrays in multilayer configurations on endocardial balloon catheters can establish conformal contact with curved tissue surfaces, support high-density spatiotemporal mapping of temperature, pressure and electrophysiological parameters and allow for programmable electrical stimulation, radiofrequency ablation and irreversible electroporation. Integrating multimodal and multiplexing capabilities into minimally invasive surgical instruments may improve surgical performance and patient outcomes.Minimally invasive surgeries involve the insertion of advanced diagnostic and therapeutic tools through small percutaneous incisions for treatment of cardiovascular diseases, cancers and other health conditions, with fast recovery times and low risks compared with those of conventional procedures 1,2 . Catheters represent one of the most compelling devices for such purposes due to their capabilities in deploying medical devices (for example, intravascular stents or heart-valve prostheses), capturing information during surgical procedures (for example, force, temperature or electrograms) and/or delivering forces, electromagnetic energy, thermal stimuli and/or biomaterials (for example, drugs, cells or nanoparticles) to targeted sites on or within soft tissues 3,4 . Although these catheter-based approaches have widespread uses in modern medicine, they suffer from (1) mechanical rigidity or insufficient compliance, leading to non-ideal interfaces with soft tissues and low coupling efficiency 5 , Han et al.

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BACKGROUND Heterogeneities of repolarization (R) across the myocardium have been invoked to explain most reentrant arrhythmias. The measurement of refractory periods (RPs) has been widely used to assess R, but conventional electrode and extrastimulus mapping techniques have not provided reliable maps of RPs. METHODS AND RESULTS Guinea pig hearts were stained with a voltage-sensitive dye to measure fluorescence (F) action potentials (APs) from 124 sites with a photodiode array. AP duration (APD) was defined as the time between depolarization (dF/dt)max and R time points (ie, the time when AP returns to baseline or some percent thereof). However, R time points are difficult to determine because AP downstrokes are often encumbered by drifting baselines and motion artifacts, which make this definition ambiguous. In optical and microelectrode recordings, the second derivative of AP downstrokes is shown to contain an easily detected, unique local maximum. The correlation between the position of this maximum (d2F/dt2)max and R has been tested during altered AP characteristics induced by changes in cycle length, ischemia, and hypoxia. Under these various modifications of the AP, the time points of (d2F/dt2)max fell at 97.0 +/- 2.1% of recovery to baseline. Extrastimulus techniques applied to (1) isolated myocytes, (2) intact hearts, and (3) mathematical simulations indicated that (d2V/dt2)max coincided with the effective RPs of APs. The coincidence of RPs and (d2V/dt2)max was valid within 5 milliseconds, for resting potentials of -75 to -90 mV and extrastimuli three times threshold voltage. CONCLUSIONS Thus, optical APs and (d2F/dt2)max can be used to map activation, R, and RPs with AP recordings from a single heartbeat.

Abstract-During failure of the sinoatrial node, the heart can be driven by an atrioventricular (AV) junctional pacemaker.The position of the leading pacemaker site during AV junctional rhythm is debated. In this study, we present evidence from high-resolution fluorescent imaging of electrical activity in rabbit isolated atrioventricular node (AVN) preparations that, in the majority of cases (11 out of 14), the AV junctional rhythm originates in the region extending from the AVN toward the coronary sinus along the tricuspid valve (posterior nodal extension, PNE). Histological and immunohistochemical investigation showed that the PNE has the same morphology and unique pattern of expression of neurofilament160 (NF160) and connexins (Cx40, Cx43, and Cx45) as the AVN itself. Block of the pacemaker current, I f , by 2 mmol/L Cs ϩ increased the AV junctional rhythm cycle length from 611Ϯ84 to 949Ϯ120 ms (meanϮSD, nϭ6, PϽ0.001). Immunohistochemical investigation showed that the principal I f channel protein, HCN4, is abundant in the PNE. As well as the AV junctional rhythm, the PNE described in this study may also be involved in the slow pathway of conduction into the AVN as well as AVN reentry, and the predominant lack of expression of Cx43 as well as the presence of Cx45 in the PNE shown could help explain its slow conduction. Key Words: ablation Ⅲ electrophysiology Ⅲ surgery Ⅲ arrhythmia Ⅲ imaging S ince Tawara's discovery of the atrioventricular node (AVN) nearly a century ago, 1 anatomists and electrophysiologists have established that the AVN is the only conduction pathway between the atria and ventricles in the normal heart. 2 The AVN has unique slow and frequencydependent conduction properties. 2 Under normal physiological conditions, the AVN determines the appropriate frequency-dependent delay of conduction between the atria and ventricles and, during atrial fibrillation, the AVN filters high-frequency excitation, thus protecting the ventricular myocardium. 3 The AVN has dual inputs (fast and slow pathways) from the atrial myocardium and this may be the substrate for AVN reentry. 4,5 The AVN also has pacemaking ability: during failure of the sinoatrial node, the heart can be driven by an atrioventricular (AV) junctional pacemaker, although the position of the leading pacemaker site is debated. 6,7 Recent application of fluorescent imaging with voltagesensitive dyes 5,8 -12 has provided new insights into the electrophysiology of the AV junction. With fluorescent imaging, we have recently shown how the fast and slow pathways of conduction support normal conduction, 9 AVN echo, 5 and AVN reentry. 12 Application of immunohistochemical imaging has shown that the expression of ion channels 13 and gap junction channel isoforms 14,15 can explain the electrophysiology of the AVN. In particular, a lack of or a low density of Na ϩ channels in the compact node (CN) can explain the slow upstroke and low amplitude of the action potential in CN. 13 Similarly, in CN, a lack of or a low density of low impedance isoforms of gap...

Nanofibrillar forms of proteins were initially recognized in the context of pathology, but more recently have been discovered in a range of functional roles in nature, including as active catalytic scaffolds and bacterial coatings. Here we show that protein nanofibrils can be used to form the basis of monodisperse microgels and gel shells composed of naturally occurring proteins. We explore the potential of these protein microgels to act as drug carrier agents, and demonstrate the controlled release of four different encapsulated drug-like small molecules, as well as the component proteins themselves. Furthermore, we show that protein nanofibril self-assembly can continue after the initial formation of the microgel particles, and that this process results in active materials with network densities that can be modulated in situ. We demonstrate that these materials are nontoxic to human cells and that they can be used to enhance the efficacy of antibiotics relative to delivery in homogeneous solution. Because of the biocompatibility and biodegradability of natural proteins used in the fabrication of the microgels, as well as their ability to control the release of small molecules and biopolymers, protein nanofibril microgels represent a promising class of functional artificial multiscale materials generated from natural building blocks.