An Accurate Fiducial Marker for Aligning EMG signals with Swallow Onset.

Swallowing involves the precise coordination of a large number of muscles. This coordination can be quantified non-invasively by electromyographic (EMG) time-series analysis of swallowing events. The temporal alignment of swallow events is critical for defining coordination patterns. Here, a new framework was developed to use the acoustic signal associated with the opening of the Eustachian tube as a fiducial marker to align EMG signals with swallowing. To investigate its accuracy, manometry, audio from the Eustachian tube, and EMG were simultaneously recorded from two participants while performing different swallowing maneuvers. Eustachian tube opening consistently occurred alongside EMG activations and within 0.025 ± 0.022 s of the gold standard manometry-determined functional swallowing onset. A comparison with two traditional EMG alignment methods based on the integrated and rectified EMG signals was then performed over eight participants. Discrepancies of between 0.2 to 0.3 s were found between the initiation of swallowing and the onset or peak EMG activity. Eustachian tube opening served as a more accurate fiducial marker for temporal data alignment, compared to the traditional EMG alignment methods that were based on EMG parameters.Clinical Relevance- The proposed method will allow EMG recordings to be directly associated with the functional onset of swallowing. This provides a more accurate foundation for time-series analysis of muscle coordination and thus the identification of EMG biomarkers associated with healthy and dysphagic swallowing.

Image-Based Tools and Analysis for Human RVOT/RV Structures.

The right-ventricular (RV) outflow tract (RVOT) and the transition to the RV free wall are recognized sources of arrhythmia in human hearts. However, we do not fully understand myocardial tissue structures in this region. Human heart tissue was processed for optical clarity, labelled with wheat-germ agglutin (WGA) and anti-Cx43, and imaged on a custom-built line scanning confocal microscope. The 3D images were analyzed for myocyte gross structures and cell morphology. There were regions of high organization as well as rapid changes to more heterogeneous regions. Preliminary cell segmentations were used to estimate cell morphology. Observed RVOT/RV structure is consistent with known arrhythmic substrates.Clinical Relevance- New views of human tissue structure enable clearer clinical understanding of arrhythmogenic activation pathways and targets for invasive treatment such as RF ablation.

Power-Controlled, Irrigated Radio-Frequency Ablation of Gastric Tissue: A Biophysical Analysis of Lesion Formation.

BACKGROUND: Radio-frequency ablation of gastric tissue is in its infancy compared to its extensive history and use in the cardiac field. AIMS: We employed power-controlled, irrigated radio-frequency ablation to create lesions on the serosal surface of the stomach to examine the impact of ablation power, irrigation, temperature, and impedance on lesion formation and tissue damage. METHODS: A total of 160 lesions were created in vivo in female weaner pigs (n = 5) using a combination of four power levels (10, 15, 20, 30 W) at two irrigation rates (2, 5 mL min-1) and with one temperature-controlled (65 °C) reference setting previously validated for electrophysiological intervention in the stomach. RESULTS: Power and irrigation rate combinations above 15 W resulted in lesions with significantly higher surface area and depth than the temperature-controlled setting. Irrigation resulted in significantly lower temperature (p < 0.001) and impedance (p < 0.001) compared to the temperature-controlled setting. No instances of perforation or tissue pop were recorded for any ablation sequence. CONCLUSION: Power-controlled, irrigated radio-frequency ablation of gastric tissue is effective in creating larger and deeper lesions at reduced temperatures than previously investigated temperature-controlled radio-frequency ablation, highlighting a substantial improvement. These data define the biophysical impact of ablation parameters in gastric tissue, and they will guide future translation toward clinical application and in silico gastric ablation modeling. Combination of ablation settings (10-30 W power, 2-5 mL min-1 irrigation) were used to create serosal spot lesions. Histological analysis of lesions quantified localized tissue damage.

Quinapril treatment curtails decline of global longitudinal strain and mechanical function in hypertensive rats.

BACKGROUND: Left ventricular (LV) global longitudinal strain (GLS) has been proposed as an early imaging biomarker of cardiac mechanical dysfunction. OBJECTIVE: To assess the impact of angiotensin-converting enzyme (ACE) inhibitor treatment of hypertensive heart disease on LV GLS and mechanical function. METHODS: The spontaneously hypertensive rat (SHR) model of hypertensive heart disease ( n  = 38) was studied. A subset of SHRs received quinapril (TSHR, n  = 16) from 3 months (mo). Wistar Kyoto rats (WKY, n  = 13) were used as controls. Tagged cardiac MRI was performed using a 4.7 T Varian preclinical scanner. RESULTS: The SHRs had significantly lower LV ejection fraction (EF) than the WKYs at 3 mo (53.0 ±â€Š1.7% vs. 69.6 ±â€Š2.1%, P  < 0.05), 14 mo (57.0 ±â€Š2.5% vs. 74.4 ±â€Š2.9%, P  < 0.05) and 24 mo (50.1 ±â€Š2.4% vs. 67.0 ±â€Š2.0%, P  < 0.01). At 24 mo, ACE inhibitor treatment was associated with significantly greater LV EF in TSHRs compared to untreated SHRs (64.2 ±â€Š3.4% vs. 50.1 ±â€Š2.4%, P  < 0.01). Peak GLS magnitude was significantly lower in SHRs compared with WKYs at 14 months (7.5% ±â€Š0.4% vs. 9.9 ±â€Š0.8%, P  < 0.05). At 24 months, Peak GLS magnitude was significantly lower in SHRs compared with both WKYs (6.5 ±â€Š0.4% vs. 9.7 ±â€Š1.0%, P  < 0.01) and TSHRs (6.5 ±â€Š0.4% vs. 9.6 ±â€Š0.6%, P  < 0.05). CONCLUSIONS: ACE inhibitor treatment curtails the decline in global longitudinal strain in hypertensive rats, with the treatment group exhibiting significantly greater LV EF and GLS magnitude at 24 mo compared with untreated SHRs.

Extended-volume image-derived models of coronary microcirculation.

OBJECTIVE: Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets. METHODS: We acquired coronary microvasculature images throughout an entire short-axis slice of a 3-month-old Wistar-Kyoto rat heart. This dataset covered 13 × 10 × 0.6 mm at a resolution of 0.933 × 0.933 × 1.866 µm and occupied 700 Gigabytes of disk space. We used chunk-based image segmentation, combined with an efficient graph generation technique, to quantify the microvasculature in the large-scale images. Specifically, we focused on the microvasculature with a vessel diameter up to 15 µm. RESULTS: Morphological data for the complete short-axis ring were extracted within 16 h using this pipeline. From the analyses, we identified that microvessel lengths in the rat coronary microvasculature varied from 6 to 300 µm. However, their distribution was heavily skewed toward shorter lengths, with a mode of 16.5 µm. In contrast, vessel diameters ranged from 3 to 15 µm and had an approximately normal distribution of 6.5 ± 2 µm. CONCLUSION: The tools and techniques from this study will serve other investigations into the microcirculation, and the wealth of data from this study will enable the analysis of biophysical mechanisms using computer models.

Anaesthesia by intravenous propofol reduces the incidence of intra-operative gastric electrical slow-wave dysrhythmias compared to isoflurane.

Gastric motility is coordinated by bioelectrical slow-wave activity, and abnormal electrical dysrhythmias have been associated with nausea and vomiting. Studies have often been conducted under general anaesthesia, while the impact of general anaesthesia on slow-wave activity has not been studied. Clinical studies have shown that propofol anaesthesia reduces postoperative nausea and vomiting (PONV) compared with isoflurane, while the underlying mechanisms remain unclear. In this study, we investigated the effects of two anaesthetic drugs, intravenous (IV) propofol and volatile isoflurane, on slow-wave activity. In vivo experiments were performed in female weaner pigs (n = 24). Zolazepam and tiletamine were used to induce general anaesthesia, which was maintained using either IV propofol (n = 12) or isoflurane (n = 12). High-resolution electrical mapping of slow-wave activity was performed. Slow-wave dysrhythmias occurred less often in the propofol group, both in the duration of the recorded period that was dysrhythmic (propofol 14 ± 26%, isoflurane 43 ± 39%, P = 0.043 (Mann-Whitney U test)), and in a case-by-case basis (propofol 3/12, isoflurane 8/12, P = 0.015 (Chi-squared test)). Slow-wave amplitude was similar, while velocity and frequency were higher in the propofol group than the isoflurane group (P < 0.001 (Student's t-test)). This study presents a potential physiological biomarker linked to recent observations of reduced PONV with IV propofol. The results suggest that propofol is a more suitable anaesthetic for studying slow-wave patterns in vivo.

Localized bioelectrical conduction block from radiofrequency gastric ablation persists after healing: safety and feasibility in a recovery model.

Gastric ablation has demonstrated potential to induce conduction blocks and correct abnormal electrical activity (i.e., ectopic slow-wave propagation) in acute, intraoperative in vivo studies. This study aimed to evaluate the safety and feasibility of gastric ablation to modulate slow-wave conduction after 2 wk of healing. Chronic in vivo experiments were performed in weaner pigs (n = 6). Animals were randomly divided into two groups: sham-ablation (n = 3, control group; no power delivery, room temperature, 5 s/point) and radiofrequency (RF) ablation (n = 3; temperature-control mode, 65°C, 5 s/point). In the initial surgery, high-resolution serosal electrical mapping (16 × 16 electrodes; 6 × 6 cm) was performed to define the baseline slow-wave activation profile. Ablation (sham/RF) was then performed in the mid-corpus, in a line around the circumferential axis of the stomach, followed by acute postablation mapping. All animals recovered from the procedure, with no sign of perforation or other complications. Two weeks later, intraoperative high-resolution mapping was repeated. High-resolution mapping showed that ablation successfully induced sustained conduction blocks in all cases in the RF-ablation group at both the acute and 2 wk time points, whereas all sham-controls had no conduction block. Histological and immunohistochemical evaluation showed that after 2 wk of healing, the lesions were in the inflammation and early proliferation phase, and interstitial cells of Cajal (ICC) were depleted and/or deformed within the ablation lesions. This safety and feasibility study demonstrates that gastric ablation can safely and effectively induce a sustained localized conduction block in the stomach without disrupting the surrounding slow-wave conduction capability.NEW & NOTEWORTHY Ablation has recently emerged as a tool for modulating gastric electrical activation and may hold interventional potential for disorders of gastric function. However, previous studies have been limited to the acute intraoperative setting. This study now presents the safety of gastric ablation after postsurgical recovery and healing. Localized electrical conduction blocks created by ablation remained after 2 wk of healing, and no perforation or other complications were observed over the postsurgical period.

The Effect of Power-Control and Irrigation Settings on Lesion Size during Radio-Frequency Ablation of Gastric Tissue.

Gastric ablation has recently emerged as a promising potential therapy for correcting bioelectrical dysrhythmias that underpin many gastrointestinal motility disorders. Despite similarities to well-developed cardiac radiofrequency (RF) ablation, gastric RF ablation is in its infancy and has thus far been limited to temperature-controlled, non-irrigated settings. The potential benefits of power-controlled and irrigated RF ablation have not been investigated in gastric tissue. In this study, RF ablation was performed in vivo in pigs ( n=5) using a range of power-control (10-30 W, 10s per point) and irrigation (2-5 ml/min) settings and compared to known temperature-controlled (65°C), non-irrigated settings. Excised tissue was stained with H&E. Lesion surface area was calculated and tissue damage was quantitatively ranked by visual assessment. The results demonstrated that irrigation allowed greater energy delivery to tissue with reduced interface temperatures compared to non-irrigated settings. Power settings above 10 W created lesions that extended through the full-thickness of the muscle layer, which suggests the parameter range that can now be used to correct gastric dysrhythmias. Clinical Relevance- This work presents the results of power-controlled, irrigated RF ablation settings applied to the in vivo porcine stomach. The relationships of both lesion area and depth to ablation dose provides an improved insight into which energy doses could provide a safe and effective therapeutic response.

Multimodal imaging shows fibrosis architecture and action potential dispersion are predictors of arrhythmic risk in spontaneous hypertensive rats.

Hypertensive heart disease (HHD) increases risk of ventricular tachycardia (VT) and ventricular fibrillation (VF). The roles of structural vs. electrophysiological remodelling and age vs. disease progression are not fully understood. This cross-sectional study of cardiac alterations through HHD investigates mechanistic contributions to VT/VF risk. Risk was electrically assessed in Langendorff-perfused, spontaneously hypertensive rat hearts at 6, 12 and 18 months, and paced optical membrane voltage maps were acquired from the left ventricular (LV) free wall epicardium. Distributions of LV patchy fibrosis and 3D cellular architecture in representative anterior LV mid-wall regions were quantified from macroscopic and microscopic fluorescence images of optically cleared tissue. Imaging showed increased fibrosis from 6 months, particularly in the inner LV free wall. Myocyte cross-section increased at 12 months, while inter-myocyte connections reduced markedly with fibrosis. Conduction velocity decreased from 12 months, especially transverse to the myofibre direction, with rate-dependent anisotropy at 12 and 18 months, but not earlier. Action potential duration (APD) increased when clustered by age, as did APD dispersion at 12 and 18 months. Among 10 structural, functional and age variables, the most reliably linked were VT/VF risk, general LV fibrosis, a measure quantifying patchy fibrosis, and non-age clustered APD dispersion. VT/VF risk related to a quantified measure of patchy fibrosis, but age did not factor strongly. The findings are consistent with the notion that VT/VF risk is associated with rate-dependent repolarization heterogeneity caused by structural remodelling and reduced lateral electrical coupling between LV myocytes, providing a substrate for heterogeneous intramural activation as HHD progresses. KEY POINTS: There is heightened arrhythmic risk with progression of hypertensive heart disease. Risk is related to increasing left ventricular fibrosis, but the nature of this relationship has not been quantified. This study is a novel systematic characterization of changes in active electrical properties and fibrotic remodelling during progression of hypertensive heart disease in a well-established animal disease model. Arrhythmic risk is predicted by several left ventricular measures, in particular fibrosis quantity and structure, and epicardial action potential duration dispersion. Age alone is not a good predictor of risk. An improved understanding of links between arrhythmic risk and fibrotic architectures in progressive hypertensive heart disease aids better interpretation of late gadolinium-enhanced cardiac magnetic resonance imaging and electrical mapping signals.

Non-Contact Intracardiac Potential Mapping Using Mesh-Based and Meshless Inverse Solvers.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and percutaneous catheter ablation is widely used to treat it. Panoramic mapping with multi-electrode catheters has been used to identify ablation targets in persistent AF but is limited by poor contact and inadequate coverage of the left atrial cavity. In this paper, we investigate the accuracy with which atrial endocardial surface potentials can be reconstructed from electrograms recorded with non-contact catheters. An in-silico approach was employed in which "ground-truth" surface potentials from experimental contact mapping studies and computer models were compared with inverse potential maps constructed by sampling the corresponding intracardiac field using virtual basket catheters. We demonstrate that it is possible to 1) specify the mixed boundary conditions required for mesh-based formulations of the potential inverse problem fully, and 2) reconstruct accurate inverse potential maps from recordings made with appropriately designed catheters. Accuracy improved when catheter dimensions were increased but was relatively stable when the catheter occupied >30% of atrial cavity volume. Independent of this, the capacity of non-contact catheters to resolve the complex atrial potential fields seen in reentrant atrial arrhythmia depended on the spatial distribution of electrodes on the surface bounding the catheter. Finally, we have shown that reliable inverse potential mapping is possible in near real-time with meshless methods that use the Method of Fundamental Solutions.

Intracardiac Inverse Potential Mapping Using the Method of Fundamental Solutions.

Introduction: Atrial fibrillation (AF) is the most prevalent cardiac dysrhythmia and percutaneous catheter ablation is widely used to treat it. Panoramic mapping with multi-electrode catheters can identify ablation targets in persistent AF, but is limited by poor contact and inadequate coverage. Objective: To investigate the accuracy of inverse mapping of endocardial surface potentials from electrograms sampled with noncontact basket catheters. Methods: Our group has developed a computationally efficient inverse 3D mapping technique using a meshless method that employs the Method of Fundamental Solutions (MFS). An in-silico test bed was used to compare ground-truth surface potentials with corresponding inverse maps reconstructed from noncontact potentials sampled with virtual catheters. Ground-truth surface potentials were derived from high-density clinical contact mapping data and computer models. Results: Solutions of the intracardiac potential inverse problem with the MFS are robust, fast and accurate. Endocardial surface potentials can be faithfully reconstructed from noncontact recordings in real-time if the geometry of cardiac surface and the location of electrodes relative to it are known. Larger catheters with appropriate electrode density are needed to resolve complex reentrant atrial rhythms. Conclusion: Real-time panoramic potential mapping is feasible with noncontact intracardiac catheters using the MFS. Significance: Accurate endocardial potential maps can be reconstructed in AF with appropriately designed noncontact multi-electrode catheters.

Myocardial mesostructure and mesofunction.

The complex and highly organized structural arrangement of some five billion cardiomyocytes directs the coordinated electrical activity and mechanical contraction of the human heart. The characteristic transmural change in cardiomyocyte orientation underlies base-to-apex shortening, circumferential shortening, and left ventricular torsion during contraction. Individual cardiomyocytes shorten ∼15% and increase in diameter ∼8%. Remarkably, however, the left ventricular wall thickens by up to 30-40%. To accommodate this, the myocardium must undergo significant structural rearrangement during contraction. At the mesoscale, collections of cardiomyocytes are organized into sheetlets, and sheetlet shear is the fundamental mechanism of rearrangement that produces wall thickening. Herein, we review the histological and physiological studies of myocardial mesostructure that have established the sheetlet shear model of wall thickening. Recent developments in tissue clearing techniques allow for imaging of whole hearts at the cellular scale, whereas magnetic resonance imaging (MRI) and computed tomography (CT) can image the myocardium at the mesoscale (100 µm to 1 mm) to resolve cardiomyocyte orientation and organization. Through histology, cardiac diffusion tensor imaging (DTI), and other modalities, mesostructural sheetlets have been confirmed in both animal and human hearts. Recent in vivo cardiac DTI methods have measured reorientation of sheetlets during the cardiac cycle. We also examine the role of pathological cardiac remodeling on sheetlet organization and reorientation, and the impact this has on ventricular function and dysfunction. We also review the unresolved mesostructural questions and challenges that may direct future work in the field.

It's clearly the heart! Optical transparency, cardiac tissue imaging, and computer modelling.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity. Four interlinked issues need to be addressed: 1) efficient clearing and labelling of heart tissue, 2) fast microscopic imaging of human-scale samples, 3) handling and processing of multi-terabyte 3D images, and 4) extraction of structural information in computationally tractable structure-based models of cardiac function. Preliminary studies show that each of these requirements can be achieved with the appropriate application and development of existing technologies.

A novel system for mapping regional electrical properties and characterizing arrhythmia in isolated intact rat atria.

Detailed global maps of atrial electrical activity are needed to understand mechanisms of atrial rhythm disturbance in small animal models of heart disease. To date, optical mapping systems have not provided enough spatial resolution across sufficiently extensive regions of intact atrial preparations to achieve this goal. The aim of this study was to develop an integrated platform for quantifying regional electrical properties and analyzing reentrant arrhythmia in a biatrial preparation. Intact atria from 6/7-mo-old female spontaneously hypertensive rats (SHRs; n = 6) were isolated and secured in a constant flow superfusion chamber at 37°C. Optical mapping was performed with the membrane-voltage dye di-4-ANEPPS using LED excitation and a scientific complementary metal-oxide semiconductor (sCMOS) camera. Programmed stimulus trains were applied from right atrial (RA) and left atrial (LA) sites to assess rate-dependent electrical behavior and to induce atrial arrhythmia. Signal-to-noise ratio was improved by sequential processing steps that included spatial smoothing, temporal filtering, and, in stable rhythms, ensemble-averaging. Activation time, repolarization time, and action potential duration (APD) maps were constructed at high spatial resolution for a wide range of coupling intervals. These data were highly consistent within and between experiments. They confirmed preferential atrial conduction pathways and demonstrated distinct medial-to-lateral APD gradients. We also showed that reentrant arrhythmias induced in this preparation were explained by the spatial variation of these electrical properties. Our new methodology provides a robust means of 1) quantifying regional electrical properties in the intact rat atria at higher spatiotemporal resolution than previously reported, and 2) characterizing reentrant arrhythmia and analyzing mechanisms that give rise to it.NEW & NOTEWORTHY Despite wide-ranging optical mapping studies, detailed information on regional atrial electrical properties in small animal models of heart disease and how these contribute to reentrant arrhythmia remains limited. We have developed a novel experimental platform that enables both to be achieved in a geometrically intact isolated rat bi-atrial preparation.

Electrocardiographic Imaging of Repolarization Abnormalities.

Background Dispersion and gradients in repolarization have been associated with life-threatening arrhythmias, but are difficult to quantify precisely from surface electrocardiography. The objective of this study was to evaluate electrocardiographic imaging (ECGI) to noninvasively detect repolarization-based abnormalities. Methods and Results Ex vivo data were obtained from Langendorff-perfused pig hearts (n=8) and a human donor heart. Unipolar electrograms were recorded simultaneously during sinus rhythm from an epicardial sock and the torso-shaped tank within which the heart was suspended. Regional repolarization heterogeneities were introduced through perfusion of dofetilide and pinacidil into separate perfusion beds. In vivo data included torso and epicardial potentials recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, and ventricular pacing. For both data sets, ECGI accurately reconstructed T-wave electrogram morphologies when compared with those recorded by the sock (ex vivo: correlation coefficient, 0.85 [0.52-0.96], in vivo: correlation coefficient, 0.86 [0.52-0.96]) and repolarization time maps (ex-vivo: correlation coefficient, 0.73 [0.63-0.83], in vivo: correlation coefficient, 0.76 [0.67-0.82]). ECGI-reconstructed repolarization time distributions were strongly correlated to those measured by the sock (both data sets, R2 ≥0.92). Although the position of the gradient was slightly shifted by 8.3 (0-13.9) mm, the mean, max, and SD between ECGI and recorded gradient values were highly correlated (R2=0.87, 0.75, and 0.86 respectively). There was no significant difference in ECGI accuracy between ex vivo and in vivo data. Conclusions ECGI reliably and accurately maps potentially critical repolarization abnormalities. This noninvasive approach allows imaging and quantifying individual parameters of abnormal repolarization-based substrates in patients with arrhythmogenesis, to improve diagnosis and risk stratification.

Evidence of structural and functional plasticity occurring within the intracardiac nervous system of spontaneously hypertensive rats.

Plasticity is a fundamental property of neurons in both the central and peripheral nervous systems, enabling rapid changes in neural network function. The intracardiac nervous system (ICNS) is an extensive network of neurons clustered into ganglionated plexi (GP) on the surface of the heart. GP neurons are the final site of neuronal control of heart rhythm, and pathophysiological remodeling of the ICNS is proposed to feature in multiple cardiovascular diseases, including heart failure and atrial fibrillation. To examine the potential role of GP neuron plasticity in atrial arrhythmia and hypertension, we developed whole cell patch clamp recording techniques from GP neurons in isolated ICNS preparations from aged control (Wistar-Kyoto) and spontaneously hypertensive rats (SHRs). Anesthetized SHRs showed frequent premature ventricular contractions and episodes of atrial arrhythmia following carbachol injection, and isolated SHR atrial preparations were susceptible to pacing induced atrial arrhythmia. Whole cell recordings revealed elevated spontaneous postsynaptic current frequency in SHR GP neurons, as well as remodeled electrophysiology, with significant decreases in action potential amplitude and half-width. SHRs also showed a parallel increase in the number of cholinergic neurons and adrenergic glomus cells in cardiac ganglia, a higher proportion of synaptic α7-subunit but not ß2-containing nicotinic receptors, and an elevation in the number of synaptic terminals onto GP neurons. Our data show that significant structural and functional plasticity occurs in the intracardiac nervous system and suggest that enhanced excitability through synaptic plasticity, together with remodeling of cardiac neuron electrophysiology, contributes to the substrate for atrial arrhythmia in hypertensive heart disease.NEW & NOTEWORTHY We have developed intracardiac neuron whole cell recording techniques in atrial preparations from control and spontaneous hypertensive rats. This has enabled the identification of significant synaptic plasticity in the intracardiac nervous system, including enhanced postsynaptic current frequency, increased synaptic terminal density, and altered postsynaptic receptors. This increased synaptic drive together with altered cardiac neuron electrophysiology could increase intracardiac nervous system excitability and contribute to the substrate for atrial arrhythmia in hypertensive heart disease.

High-resolution 3D imaging and topological mapping of the lymph node conduit system.

The conduit network is a hallmark of lymph node microanatomy, but lack of suitable imaging technology has prevented comprehensive investigation of its topology. We employed an extended-volume imaging system to capture the conduit network of an entire murine lymph node (comprising over 280,000 segments). The extensive 3D images provide a comprehensive overview of the regions supplied by conduits, including perivascular sleeves and distinctive "follicular reservoirs" within B cell follicles, surrounding follicular dendritic cells. A 3D topology map of conduits within the T-cell zone showed homogeneous branching, but conduit density was significantly higher in the superficial T-cell zone compared with the deep zone, where distances between segments are sufficient for T cells to lose contact with fibroblastic reticular cells. This topological mapping of the conduit anatomy can now aid modeling of its roles in lymph node function, as we demonstrate by simulating T-cell motility in the different T-cell zones.

Microstructurally Motivated Constitutive Modeling of Heart Failure Mechanics.

Heart failure (HF) is one of the leading causes of death worldwide. HF is associated with substantial microstructural remodeling, which is linked to changes in left ventricular geometry and impaired cardiac function. The role of myocardial remodeling in altering the mechanics of failing hearts remains unclear. Structurally based constitutive modeling provides an approach to improve understanding of the relationship between biomechanical function and tissue organization in cardiac muscle during HF. In this study, we used cardiac magnetic resonance imaging and extended-volume confocal microscopy to quantify the remodeling of left ventricular geometry and myocardial microstructure of healthy and spontaneously hypertensive rat hearts at the ages of 12 and 24 months. Passive cardiac mechanical function was characterized using left ventricular pressure-volume compliance measurements. We have developed a, to our knowledge, new structurally based biomechanical constitutive equation built on parameters quantified directly from collagen distributions observed in confocal images of the myocardium. Three-dimensional left ventricular finite element models were constructed from subject-specific in vivo magnetic resonance imaging data. The structurally based constitutive equation was integrated into geometrically subject-specific finite element models of the hearts and used to investigate the underlying mechanisms of ventricular dysfunction during HF. Using a single pair of material parameters for all hearts, we were able to produce compliance curves that reproduced all of the experimental compliance measurements. The value of this study is not limited to reproducing the mechanical behavior of healthy and diseased hearts, but it also provides important insights into the structure-function relationship of diseased myocardium that will help pave the way toward more effective treatments for HF.

Reconstruction of coronary circulation networks: A review of methods.

Building anatomically accurate models of the coronary vascular system enables potentially deeper understandings of coronary circulation. To achieve this, (a) images at different levels of vascular network-arteries, arterioles, capillaries, venules, and veins-need to be obtained through suitable imaging modalities; and (b) from images, morphological and topological information needs to be extracted using image processing techniques. While there are several modalities that enable the imaging of large vessels, microcirculation imaging-capturing vessels having diameter lesser than 100 µm-has to date been typically confined to small regions of the heart. This spatially limited microcirculatory information has often been used within cardiac models, with the potentially erroneous assumption that it is representative of the whole organ. However, with the recent advancements in imaging and image processing, it is rapidly becoming feasible to acquire, process, and quantify microcirculation data at the scale of whole organ. In this review, we summarize the progress toward this goal followed through a presentation of the current state-of-the-art imaging and image processing techniques in the context of coronary microcirculation extraction, prominently but not exclusively, from small animals.

How Accurate Is Inverse Electrocardiographic Mapping? A Systematic In Vivo Evaluation.

BACKGROUND: Inverse electrocardiographic mapping reconstructs cardiac electrical activity from recorded body surface potentials. This noninvasive technique has been used to identify potential ablation targets. Despite this, there has been little systematic evaluation of its reliability. METHODS: Torso and ventricular epicardial potentials were recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, epicardial, and endocardial ventricular pacing (70 records in total). Body surface and cardiac electrode positions were determined and registered using magnetic resonance imaging. Epicardial potentials were reconstructed during ventricular activation using experiment-specific magnetic resonance imaging-based thorax models, with homogeneous or inhomogeneous (lungs, skeletal muscle, fat) electrical properties. Coupled finite/boundary element methods and a meshless approach based on the method of fundamental solutions were compared. Inverse mapping underestimated epicardial potentials >2-fold (P<0.0001). RESULTS: Mean correlation coefficients for reconstructed epicardial potential distributions ranged from 0.60±0.08 to 0.64±0.07 across all methods. Epicardial electrograms were recovered with reasonable fidelity at ≈50% of sites (median correlation coefficient, 0.69-0.72), but variation was substantial. General activation spread was reproduced (median correlation coefficient, 0.72-0.78 for activation time maps after spatio-temporal smoothing). Epicardial foci were identified with a median location error ≈16 mm (interquartile range, 9-29 mm). Inverse mapping with meshless method of fundamental solutions was better than with finite/boundary element methods, and the latter were not improved by inclusion of inhomogeneous torso electrical properties. CONCLUSIONS: Inverse potential mapping provides useful information on the origin and spread of epicardial activation. However the spatio-temporal variability of recovered electrograms limit resolution and must constrain the accuracy with which arrhythmia circuits can be identified independently using this approach.