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On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. Although alternative slow-wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (Vm) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256 × 256 pixel cameras. Motion artifact was corrected using a marker-based motion-tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and Vm morphology against alternative nonoptical technologies. Nonantegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and nonantegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored. NEW & NOTEWORTHY: This article introduces a novel method for imaging gastric electrophysiology and mechanical function simultaneously in anesthetized, open-abdomen pigs. We demonstrate it by observing propagating slow-wave depolarization and repolarization along with the strength, spatial distribution, and direction of contractions. In addition, we observe that in this animal preparation, slow waves often do not propagate from the proximal to distal stomach and are frequently asymmetric between the anterior and posterior sides of the stomach. [ABSTRACT FROM AUTHOR]

Computer modeling of cardiac propagation suggests that curvature of muscle fibers modulates conduction velocity (CV). The effect could be involved in arrhythmogenesis by altering the dynamics of reentrant wavefronts or by causing propagation block. To verify the existence of this effect experimentally, we measured CV in anisotropic neonatal rat ventricular myocyte monolayers. The orientation of the cells was directed by scratches machined into plastic coverslips. Each substrate contained a region in which scratch radius of curvature varied from 0.25 to 1.0 cm. The CV anisotropy ratio (longitudinal CV/transverse CV in straight fiber regions) was 2.3 [+ or -] 0.3 (n : 38). We initiated wavefronts transverse to fibers with the fibers either curving toward or away from the wavefronts. Action potentials were recorded using a potentiometric dye and a video camera. Propagation was faster (p = 0.0003) when fibers curved toward wavefronts than when fibers curved in the opposite direction. The mean CV difference was 0.38 [+ or -] 0.44 cm/s (n = 24), which is 3.5% of nominal straight fiber transverse CV (11.0 [+ or -] 3.2 cm/s). The effect was also present (p = 0.07) when pacing was slowed from 350 to 500 ms (n = 6). In a control group (n = 8) with uncurved fibers, CV was the same in both directions (p = NS). We conclude that fiber curvature is a factor in modulating cardiac propagation. Index Terms--Anisotropy, arrhythmia, cardiomyocytes, electro-physiology, optical mapping.

Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution (n = 6) or normal Tyrode solution as a control (n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 x 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 [+ or -] 1.5 vs. 9.2 [+ or -] 3.2 rain, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excitable, but only short episodes of VF could be reinduced. Endocardial activation rates were similar during the first 2 min of LDVF for Lugol-ablated and control hearts but were significantly slower in Lugol hearts by 3 min. In control hearts, the endocardium activated more rapidly than the epicardium after 4 rain of LDVF with wave fronts propagating most often from the endocardium to epicardium. No difference in transmural activation rate or wave front direction was observed in Lugol hearts. Ablation of the subendocardium hastens VF spontaneous termination and alters VF activation sequences, suggesting that Purkinje fibers are important in the maintenance of LDVF. electrophysiology; mapping; Lugol ablation; activation rate gradient

During ventricular fibrillation (VF), electrical activation waves are fragmented, and the heart cannot contract in synchrony. It has been proposed that VF waves emanate from stable periodic sources (often called 'mother rotors'). The objective of the present study was to determine if stable rotors are consistently present on the epicardial surface of hearts comparable in size to human hearts. Using new optical mapping technology, we imaged VF from nearly the entire ventricular surface of six isolated swine hearts. Using newly developed pattern analysis algorithms, we identified and tracked VF wave fronts and phase singularities (PS; the pivot point of a reentrant wave front). We introduce the notion of a compound rotor in which the rotor's central PS can change and describe an algorithm for automatically identifying such patterns. This prevents rotor lifetimes from being inappropriately abbreviated by wave front fragmentation and collision events near the PS. We found that stable epicardial rotors were not consistently present during VF: only 1 of 17 VF episodes contained a compound rotor that lasted for the entire mapped interval of 4 s. However, shorter-lived rotors were common; 12.2 (SD 3.3) compound rotors with lifetime >200 ms were visible on the epicardium at any given instant. We conclude that epicardial mother rotors do not drive VF in this experimental model; if mother rotors do exist, they are intramural or septal. This paucity of persistent rotors suggests that individual rotors will eventually terminate by themselves and therefore that the continual formation of new rotors is critical for VF maintenance. reentry; optical mapping

Optical mapping of electrical activity from the surface of the heart is a powerful tool for studying complex arrhythmias. However, a limitation of traditional optical mapping is that the mapped region is restricted to the field of view of the sensor, which makes it difficult to track electrical waves as they drift in and out of view. To address this, we developed an optical system that panoramically maps epicardial electrical activity in three dimensions. The system was engineered to accomodate hearts comparable in size to human hearts. It is comprised of a surface scanner that measures epicardial geometry and a panoramic fluorescence imaging system that records electrical activity. Custom software texture maps the electrical data onto a reconstructed epicardial surface. The result is a high resolution, spatially contiguous, mapping dataset. In addition, the three-dimensional positions of the recording sites are known, making it possible to accurately measure parameters that require geometric information, such as propagation velocity. In this paper, we describe the system and demonstrate it by mapping a swine heart. Index Terms--Cardiac arrhythmias, cardiac electrophysiology, optical mapping, panoramic, three-dimensional reconstruction.

Although resuscitation for sudden cardiac arrest attempts are frequently not instituted for several minutes after the onset of ventricular fibrillation (VF), previous mapping studies have examined only the first 40 s of VF or have involved isolated perfused hearts that did not become ischemic during VF. We applied quantitative pattern analysis to mapping data throughout the first 10 min of VF acquired from a 21 x 24 unipolar electrode array located on the ventricular epicardium of six open-chest dogs. The following twelve descriptors were continuously quantified: 1) number of wavefronts, 2) incidence of reentry, 3) wavefront propagation velocity, 4) incidence of breakthrough/focus, 5) incidence of block, 6) mean area activated by the wavefronts, 7) wavefront fractionations, 8) wavefront collisions, 9) multiplicity index, 10) repeatability, 11) negative peak rate of voltage change, and 12) peak frequency of activation. Cluster analysis of these descriptors divided VF into five stages (stages i-v). The values of most descriptors (except block and breakthrough incidence) increased during stage i (1-11 s after VF induction) and maintained high values with rapid dynamic fluctuations during stage ii (12-62 s). Descriptors changed quickly to values indicating greater organization during stage iii (63-86 s), decreased steadily during stage iv (87-310 s), and approached zero during ,stage v (311-600 s). There was a high incidence of reentry just before, during, and after stage iii. In conclusion, during the first 10 min, VF can be divided into five stages according to the evolution of electrophysiological characteristics. All of the parameters show a rapid deterioration during VF, except for a temporary reversal ~1 min after induction when activation briefly became more organized. Thus a quantitative description of activation does not uniformly decrease as VF progresses, but undergo rapid changes and exhibit a brief interval of increased organization after ~1 min of VF. Further studies are warranted to determine whether these changes, particularly the increased organization of stage iii, have clinical consequences, such as an alteration in defibrillation efficacy. cardiac mapping; electrophysiology

Much of the research into the mechanisms of ventricular fibrillation (VF) employs high-resolution mapping of electrical activation and recovery patterns. We previously developed a method for analyzing electrically mapped VF patterns that was based on identifying individual VF wavefronts. We now introduce a related method designed to take into account the information on repolarization that is present in optically mapped VF data. The new method first converts raw fluorescence data to an angular variable that tracks the phase of the mapped tissue through the depolarization-repolarization cycle. We define wavefronts in this context as isolines of phase that terminate either at boundaries or at singular points within the phase field. These singularities are the pivots of functional reentry and are important determinants of VF patterns. We parameterize VF by constructing data structures that describe wavefronts and singularities and also maintain wavefront-wavefront, wavefront-singularity, and singularity-singularity relationships. We describe one important application of this parameterization, which is to identify, localize, and characterize the importance of occurrences of propagation block during VF. Index Terms--Arrhythmia, electrophysiology, graph, reentry, wavebreak.

We tested whether the interventions typically required for optical mapping affect activation patterns during ventricular fibrillation (VF). A 21 x 24 unipolar electrode array (1.5 mm spacing) was sutured to the left ventricular epicardium of 16 anesthetized pigs, and four episodes of electrically induced VF (30-s duration) were recorded. The hearts were then rapidly excised and connected to a Langendorff perfusion apparatus. Four of the hearts were controls, in which 24 additional VF episodes were then mapped. In the remaining 12 hearts, four VF episodes were mapped after isolation, four more episodes were mapped after exposure to the voltage-sensitive dye di-4-ANEPPS, and six more episodes were mapped after exposure to the electromechanical uncoupling agents diacetyl monoxime (DAM; 20 mmol/l, n = 6) or cytochalasin D (CytoD; 10 [micro]mol/l, n = 6). VF episodes were separated by 4 min. VF activation patterns were quantified using custom pattern analysis algorithms. From comparisons with time-corrected control data, all interventions significantly changed VF patterns. Most changes were broadly consistent with slowing and regularization due to loss of excitability. Heart isolation had the largest effect on VF patterns, followed by CytoD, DAM, and dye. activation pattern; optical mapping; di-4-ANEPPS; diacetyl monoxime; cytochalasin D

It is commonly thought that lethal tachyarrhythmias, such as ventricular fibrillation (VF), are perpetuated by functional reentry, which occurs when an activation wave blocks and rotates around tissue that is excitable (i.e., functional block). Electrograms recorded near these regions typically contain two sequential deflections representing activation on either side of the block. By detecting these 'double potentials,' we hypothesize that functional block can be detected by a single electrode. Methods: Unipolar electrograms were recorded from a 24 x 21 mapping array on the intact ventricular epicardium of five pigs during electrically-induced VF. The short time Fourier Transform (STFT) of each electrogram was analyzed to identify double potentials. To evaluate the performance of the STFT algorithm, conduction block was located in activation maps using a minimum conduction velocity criterion (10 cm/s) and then compared to the results of the STFT algorithm. Results: The STFT algorithm detected conduction block with a sensitivity of 0.74 [+ or -] 0.12 and a specificity of 0.99 [+ or -] 0.00. Conclusion: We have developed an automated algorithm that can detect functional block during VF from a single electrode recording. Possible applications include fast, objective identification of block in mapping data and realtime localization of reentrant substrates using mapping catheters. Index Terms - Functional conduction block, double potential, short time Fourier transform (STFT), ventricular fibrillation (VF).

An automated method to estimate vector fields of propagation velocity from observed epicardial extracellular potentials is introduced. The method relies on fitting polynomial surfaces T(x, y) to the space-time (x, y, t) coordinates of activity. Both speed and direction of propagation are computed from the gradient of the local polynomial surface. The components of velocity, which are total derivatives, are expressed in terms of the partial derivatives which comprise the gradient of T. The method was validated on two-dimensional (2-D) simulations of propagation and then applied to cardiac mapping data. Conduction velocity was estimated at multiple epicardial locations during sinus rhythm, pacing, and ventricular fibrillation (VF) in pigs. Data were obtained via a 528-channel mapping system from 23 x 22 and 24 x 21 arrays of unipolar electrodes sutured to the right ventricular epicardium. Velocity estimates are displayed as vector fields and are used to characterize propagation qualitatively and quantitatively during both simple and complex rhythms. Index Terms - Cardiac mapping, conduction velocity, fibrillation, vector fields.

A new computational method was developed for modeling the effects of the geometric complexity, nonuniform muscle fiber orientation, and material inhomogeneity of the ventricular wall on cardiac impulse propagation. The method was used to solve a modification to the FitzHugh-Nagumo system of equations. The geometry, local muscle fiber orientation, and material parameters of the domain were defined using linear Lagrange or cubic Hermite finite element interpolation. Spatial variations of time-dependent excitation and recovery variables were approximated using cubic Hermite finite element interpolation, and the governing finite element equations were assembled using the collocation method. To overcome the deficiencies of conventional collocation methods on irregular domains, Galerkin equations for the no-flux boundary conditions were used instead of collocation equations for the boundary degrees-of-freedom. The resulting system was evolved using an adaptive Runge-Kutta method. Converged two-dimensional simulations of normal propagation showed that this method requires less CPU time than a traditional finite difference discretization. The model also reproduced several other physiologic phenomena known to be important in arrhythmogenesis including: Wenckebach periodicity, slowed propagation and unidirectional block due to wavefront curvature, reentry around a fixed obstacle, and spiral wave reentry. In a new result, we observed wavespeed variations and block due to nonuniform muscle fiber orientation. The findings suggest that the finite element method is suitable for studying normal and pathological cardiac activation and has significant advantages over existing techniques.

We developed a new method for fabricating plunge needle electrodes for use in cardiac mapping. The needles have 12 electrodes with 1-mm spacing, are 0.5 mm in diameter, and are fabricated from fiberglass reinforced epoxy. They are stiff enough to be easily inserted into beating hearts and durable enough to be reused many times. We found that these new needles elicit smaller, more quickly resolving injury potentials, and when inserted in a row with 2-mm spacing, disrupt ventricular fibrillation activation patterns less than traditional steel needles. Index Terms--Plunge needle, unipolar mapping, ventricular fibrillation.

This paper examines relationships between trans-membrane potential ([V.sub.m]), [[[Ca.sup.2+]].sub.i] dependent membrane ionic currents, and [[[Ca.sup.2+]].sub.i] handling by the sarcoplasmic reticulum (SR) in a two-dimensional model of cardiac tissue. Luo-Rudy dynamic (LRd) membrane equations were used because they include detailed formulations for triggered SR [Ca.sup.2+] release dependent on membrane [Ca.sup.2+] influx (CICR) and for spontaneous SR [Ca.sup.2+] release following calsequestrin buffer overload (SCR). Reentry's rapid rate (110-ms cycle length) elevated [[[Ca.sup.2+]].sub.i] and limited CICR, which in turn promoted SCR that occurred at intervals of 320-350 ms, was preferential at sites located inside the functional center, and destabilized the reentrant activation sequence. Although adjustment of LRd parameters for SR [Ca.sup.2+] modified SCR interval and peak [[[Ca.sup.2+]].sub.i] in voltage clamp simulations with a command waveform representing [V.sub.m] time course within the functional center, SCR persisted. Using the same command waveform, SCR also occurred with an alternate SR [Ca.sup.2+] formulation that represented subcellular details underlying CICR. LRd parameter adjustments to promote CICR and limit SCR in subsequent reentry simulations failed to eliminate SCR completely, as they modulated SCR intervals in a manner consistent with the voltage clamp simulations. Taken together, our findings support a destabilizing influence of functional reentry on [[[Ca.sup.2+]].sub.i] handling. However, [[[Ca.sup.2+]].sub.i] instabilities did not always fractionate depolarization wavefronts during reentry. Fractionation depended, in part, upon CICR and SCR parameters in the LRd formulation for SR [Ca.sup.2+] release. Index Terms--Action potential, arrhythmia, calcium induced calcium release, numerical simulations, spontaneous calcium release.