Reconsideration of the Gastroparetic Syndrome.

PURPOSE OF REVIEW: Gastroparesis is a chronic disorder characterized by a constellation of foregut symptoms, including postprandial nausea, vomiting, distension, epigastric pain, and regurgitation in the absence of gastric outlet obstruction. Despite considerable research over the past decades, there remains to be only nominal understanding of disease classification, diagnostic criteria, pathogenesis, and preferred therapy. RECENT FINDINGS: We critically reassess current approaches for disease identification and stratification, theories of causation, and treatment for gastroparesis. Gastric scintigraphy, long considered a diagnostic standard, has been re-evaluated in light of evidence showing low sensitivity, whereas newer testing modalities are incompletely validated. Present concepts of pathogenesis do not provide a unified model linking biological impairments with clinical manifestations, whereas available pharmacological and anatomical treatments lack explicit selection criteria or evidence for sustained effectiveness. We propose a disease model that embodies the re-programming of distributed neuro-immune interactions in the gastric wall by inflammatory perturbants. These interactions, combined with effects on the foregut hormonal milieu and brain-gut axis, are postulated to generate the syndromic attributes characteristically linked with gastroparesis. Research linking models of immunopathogenesis with diagnostic and therapeutic paradigms will lead to reclassifications of gastroparesis that guide future trials and technological developments. KEY POINTS: • The term gastroparesis embodies a heterogenous array of symptoms and clinical findings based on a complex assimilation of afferent and efferent mechanisms, gastrointestinal locations, and pathologies. • There currently exists no single test or group of tests with sufficient capacity to be termed a definitional standard for gastroparesis. • Present research regarding pathogenesis suggests the importance of immune regulation of intrinsic oscillatory activity involving myenteric nerves, interstitial cells of Cajal, and smooth muscle cells. • Prokinetic pharmaceuticals remain the mainstay of management, although novel treatments are being studied that are directed to alternative muscle/nerve receptors, electromodulation of the brain-gut axis, and anatomical (endoscopic, surgical) interventions.

Lipid and smooth muscle architectural pathology in the rabbit atherosclerotic vessel wall using Q-space cardiovascular magnetic resonance.

BACKGROUND: Atherosclerosis is an arterial vessel wall disease characterized by slow, progressive lipid accumulation, smooth muscle disorganization, and inflammatory infiltration. Atherosclerosis often remains subclinical until extensive inflammatory injury promotes vulnerability of the atherosclerotic plaque to rupture with luminal thrombosis, which can cause the acute event of myocardial infarction or stroke. Current bioimaging techniques are unable to capture the pathognomonic distribution of cellular elements of the plaque and thus cannot accurately define its structural disorganization. METHODS: We applied cardiovascular magnetic resonance spectroscopy (CMRS) and diffusion weighted CMR (DWI) with generalized Q-space imaging (GQI) analysis to architecturally define features of atheroma and correlated these to the microscopic distribution of vascular smooth muscle cells (SMC), immune cells, extracellular matrix (ECM) fibers, thrombus, and cholesteryl esters (CE). We compared rabbits with normal chow diet and cholesterol-fed rabbits with endothelial balloon injury, which accelerates atherosclerosis and produces advanced rupture-prone plaques, in a well-validated rabbit model of human atherosclerosis. RESULTS: Our methods revealed new structural properties of advanced atherosclerosis incorporating SMC and lipid distributions. GQI with tractography portrayed the locations of these components across the atherosclerotic vessel wall and differentiated multi-level organization of normal, pro-inflammatory cellular phenotypes, or thrombus. Moreover, the locations of CE were differentiated from cellular constituents by their higher restrictive diffusion properties, which permitted chemical confirmation of CE by high field voxel-guided CMRS. CONCLUSIONS: GQI with tractography is a new method for atherosclerosis imaging that defines a pathological architectural signature for the atheromatous plaque composed of distributed SMC, ECM, inflammatory cells, and thrombus and lipid. This provides a detailed transmural map of normal and inflamed vessel walls in the setting of atherosclerosis that has not been previously achieved using traditional CMR techniques. Although this is an ex-vivo study, detection of micro and mesoscale level vascular destabilization as enabled by GQI with tractography could increase the accuracy of diagnosis and assessment of treatment outcomes in individuals with atherosclerosis.

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility.

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.

Ablation of the calpain-targeted site in cardiac myosin binding protein-C is cardioprotective during ischemia-reperfusion injury.

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is essential for normal heart function and protects the heart from ischemia-reperfusion (I/R) injury. It is known that protein kinase-A (PKA)-mediated phosphorylation of cMyBP-C prevents I/R-dependent proteolysis, whereas dephosphorylation of cMyBP-C at PKA sites correlates with its degradation. While sites on cMyBP-C associated with phosphorylation and proteolysis co-localize, the mechanisms that link cMyBP-C phosphorylation and proteolysis during cardioprotection are not well understood. Therefore, we aimed to determine if abrogation of cMyBP-C proteolysis in association with calpain, a calcium-activated protease, confers cardioprotection during I/R injury. Calpain is activated in both human ischemic heart samples and ischemic mouse myocardium where cMyBP-C is dephosphorylated and undergoes proteolysis. Moreover, cMyBP-C is a substrate for calpain proteolysis and cleaved by calpain at residues 272-TSLAGAGRR-280, a domain termed as the calpain-target site (CTS). Cardiac-specific transgenic (Tg) mice in which the CTS motif was ablated were bred into a cMyBP-C null background. These Tg mice were conclusively shown to possess a normal basal structure and function by analysis of histology, electron microscopy, immunofluorescence microscopy, Q-space MRI of tissue architecture, echocardiography, and hemodynamics. However, the genetic ablation of the CTS motif conferred resistance to calpain-mediated proteolysis of cMyBP-C. Following I/R injury, the loss of the CTS reduced infarct size compared to non-transgenic controls. Collectively, these findings demonstrate the physiological significance of calpain-targeted cMyBP-C proteolysis and provide a rationale for studying inhibition of calpain-mediated proteolysis of cMyBP-C as a therapeutic target for cardioprotection.

Nitrogen dioxide reducing ascorbic acid technologies in the ventilator circuit leads to uniform NO concentration during inspiration.

Conventional inhaled NO systems deliver NO by synchronized injection or continuous NO flow in the ventilator circuitry. Such methods can lead to variable concentrations during inspiration that may differ from desired dosing. NO concentrations in these systems are generally monitored through electrochemical methods that are too slow to capture this nuance and potential dosing error. A novel technology that reduces NO2 into NO via low-resistance ascorbic-acid cartridges just prior to inhalation has recently been described. The gas volume of these cartridges may enhance gas mixing and reduce dosing inconsistency throughout inhalation. The impact of the ascorbic-acid cartridge technology on NO concentration during inspiration was characterized through rapid chemiluminescence detection during volume control ventilation, pressure control ventilation, synchronized intermittent mandatory ventilation and continuous positive airway pressure using an in vitro lung model configured to simulate the complete uptake of NO. Two ascorbic acid cartridges in series provided uniform and consistent dosing during inspiration during all modes of ventilation. The use of one cartridge showed variable inspiratory concentration of NO at the largest tidal volumes, whereas the use of no ascorbic acid cartridge led to highly inconsistent NO inspiratory waveforms. The use of ascorbic acid cartridges also decreased breath-to-breath variation in SIMV and CPAP ventilation. The ascorbic-acid cartridges, which are designed to convert NO2 (either as substrate or resulting from NO oxidation during injection) into NO, also provide the benefit of minimizing the variation of inhaled NO concentration during inspiration. It is expected that the implementation of this method will lead to more consistent and predictable dosing.

Patterns of intersecting fiber arrays revealed in whole muscle with generalized Q-space imaging.

The multiscale attributes of mammalian muscle confer significant challenges for structural imaging in vivo. To achieve this, we employed a magnetic resonance method, termed "generalized Q-space imaging", that considers the effect of spatially distributed diffusion-weighted magnetic field gradients and diffusion sensitivities on the morphology of Q-space. This approach results in a subvoxel scaled probability distribution function whose shape correlates with local fiber orientation. The principal fiber populations identified within these probability distribution functions can then be associated by streamline methods to create multivoxel tractlike constructs that depict the macroscale orientation of myofiber arrays. We performed a simulation of Q-space input parameters, including magnetic field gradient strength and direction, diffusion sensitivity, and diffusional sampling to determine the optimal achievable fiber angle separation in the minimum scan time. We applied this approach to resolve intravoxel crossing myofiber arrays in the setting of the human tongue, an organ with anatomic complexity based on the presence of hierarchical arrays of intersecting myocytes. Using parameters defined by simulation, we imaged at 3T the fanlike configuration of the human genioglossus and the laterally positioned merging fibers of the styloglossus, inferior longitudinalis, chondroglossus, and verticalis. Comparative scans of the excised mouse tongue at 7T demonstrated similar midline and lateral crossing fiber patterns, whereas histological analysis confirmed the presence and distribution of these myofiber arrays at the microscopic scale. Our results demonstrate a magnetic resonance method for acquiring and displaying diffusional data that defines highly ordered myofiber patterns in architecturally complex tissue. Such patterns suggest inherent multiscale fiber organization and provide a basis for structure-function analyses in vivo and in model tissues.

Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) selectively dilates pulmonary blood vessels, reduces pulmonary vascular resistance (PVR), and enhances ventilation-perfusion matching. However, existing modes of delivery for the treatment of chronic pulmonary hypertension are limited due to the bulk and heft of large tanks of compressed gas. We present a novel system for the generation of inhaled NO that is based on the initial heat-induced evaporation of liquid N2O4 into gas phase NO2 followed by the room temperature reduction to NO by an antioxidant, ascorbic acid cartridge just prior to inhalation. The biologic effects of NO generated from liquid N2O4 were compared with the effects of NO gas, on increased mean pulmonary artery pressure (mPAP) and PVR in a hypoxemic (FiO2 15%) swine model of pulmonary hypertension. We showed that NO concentration varied directly with the fixed cross sectional flow of the outflow aperture when studied at temperatures of 45, 47.5 and 50°C and was independent of the rate of heating. Liquid N2O4-sourced NO at 1, 5, and 20 ppm significantly reduced the elevated mPAP and PVR induced by experimental hypoxemia and was biologically indistinguishable from gas source NO in this model. These experiments show that it is feasible to generate highly purified NO gas from small volumes of liquid N2O4 at concentrations sufficient to lower mPAP and PVR in hypoxemic swine, and suggest that a miniaturized ambulatory system designed to generate biologically active NO from liquid N2O4 is achievable.

IL-1ß-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling.

The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1ß increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1ß also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1ß induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1ß induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.

Right Ventricular Architectural Remodeling and Functional Adaptation in Pulmonary Hypertension.

BACKGROUND: Global indices of right ventricle (RV) function provide limited insights into mechanisms underlying RV remodeling in pulmonary hypertension (PH). While RV myocardial architectural remodeling has been observed in PH, its effect on RV adaptation is poorly understood. METHODS: Hemodynamic assessments were performed in 2 rodent models of PH. RV free wall myoarchitecture was quantified using generalized Q-space imaging and tractography analyses. Computational models were developed to predict RV wall strains. Data from animal studies were analyzed to determine the correlations between hemodynamic measurements, RV strains, and structural measures. RESULTS: In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RV free wall (139º versus 97º; P=0.029), preserved global circumferential strain, and exhibited less reduction in right ventricular-pulmonary arterial coupling (0.029 versus 0.017 mm/mm Hg; P=0.037). Helical range correlated positively with coupling (P=0.036) and stroke volume index (P<0.01). Coupling correlated with global circumferential strain (P<0.01) and global radial strain (P<0.01) but not global longitudinal strain. CONCLUSIONS: Data analysis suggests that adaptive RV architectural remodeling could improve RV function in PH. Our findings suggest the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.

Two dimensional computational model coupling myoarchitecture-based lingual tissue mechanics with liquid bolus flow during oropharyngeal swallowing.

Biomechanical relationships involving lingual myoanatomy, contractility, and bolus movement are fundamental properties of human swallowing. To portray the relationship between lingual deformation and bolus flow during swallowing, a weakly one-way solid-fluid finite element model (FEM) was derived employing an elemental mesh aligned to magnetic resonance diffusional tractography (Q-space MRI, QSI) of the human tongue, an arbitrary Lagrangian-Eulerian (ALE) formulation with remeshing to account for the effects of lingual surface (boundary) deformation, an implementation of patterned fiber shortening, and a computational visualization of liquid bolus flow. Representing lingual tissue deformation in terms of its 2D principal Lagrangian strain in the mid-sagittal plane, we demonstrated that the swallow sequence was characterized by initial superior-anterior expansion directed towards the hard palate, followed by sequential, radially directed, contractions of the genioglossus and verticalis to promote lingual rotation (lateral perspective) and propulsive displacement. We specifically assessed local bolus velocity as a function of viscosity (perfect slip conditions) and observed that a low viscosity bolus (5 cP) exhibited maximal displacement, surface spreading and local velocity compared to medium (110 cP, 300 cP) and high (525 cP) viscosity boluses. Analysis of local nodal velocity revealed that all bolus viscosities exhibited a bi-phasic progression, with the low viscosity bolus being the most heterogeneous and fragmented and the high viscosity bolus being the most homogenous and cohesive. Intraoral bolus cohesion was depicted in terms of the distributed velocity gradient, with higher gradients being associated with increased shear rate and bolus fragmentation. Lastly, we made a sensitivity analysis on tongue stiffness and contractility by varying the degree of extracellular matrix (ECM) stiffness through effects on the Mooney-Rivlin derived passive matrix and by varying maximum tetanized isometric stress, and observed that a graded increase of ECM stiffness was associated with reduced bolus spreading, posterior displacement, and surface velocity gradients, whereas a reduction of global contractility resulted in a graded reduction of obtainable accommodation volume, absent bolus spreading, and loss of posterior displacement. We portray a unidirectionally coupled solid-liquid FEM which associates myoarchitecture-based lingual deformation with intra-oral bolus flow, and deduce that local elevation of the velocity gradient correlates with bolus fragmentation, a precondition believed to be associated with aspiration vulnerability during oropharyngeal swallowing.

Use of ultra pure nitric oxide generated by the reduction of nitrogen dioxide to reverse pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) has the capacity to selectively dilate pulmonary blood vessels, and thus enhance the matching of ventilation and perfusion, improve oxygenation and decrease pulmonary hypertension. However, existing approaches for the administration of inhaled NO are associated with the co-delivery of potentially toxic concentrations of nitrogen dioxide (NO2) due to the oxidation of NO in oxygen rich environments. We tested the ability of a novel methodology for generating highly purified NO through the reduction of NO2 by ascorbic acid to reverse pulmonary hypertension. In vitro testing demonstrated that the NO output of the novel device is ultrapure and free of NO2. An in vivo hypoxemic swine model of pulmonary hypertension was used to examine the dose response to NO in terms of pulmonary pressures and pulmonary vascular resistance. Pulmonary hypertension was induced by lowering inspired oxygen to 15% prior to treatment with inhaled ultra purified NO (1, 5, 20, and 80PPM). Hypoxemia increased mean pulmonary artery pressures and pulmonary vascular resistance. Inhaled ultra purified NO doses (down to 1PPM) show a marked reduction of hypoxemia-induced pulmonary vascular resistance. These experiments demonstrate a simple and robust method to generate purified inhaled NO that is devoid of NO2 and capable of reversing hypoxemia induced pulmonary hypertension.

Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a syndrome diagnosed by increased mean pulmonary artery (PA) pressure and resistance and normal pulmonary capillary wedge pressure. PAH is characterized pathologically by distal pulmonary artery remodeling, increased pulmonary vascular resistance, and plexiform lesions (PLs). Right ventricular fibrosis and hypertrophy, leading to right ventricular failure, are the main determinants of mortality in PAH. Recent work suggests that right ventricular fibrosis results from resident cardiac fibroblast activation and conversion to myofibroblasts, leading to replacement of contractile cardiomyocytes with nondistensible tissue incapable of conductivity or contractility. However, the origins, triggers, and consequences of myofibroblast expansion and its pathophysiological relationship with PAH are unclear. Recent advances indicate that signals generated by adaptive and innate immune cells may play a role in right ventricular fibrosis and remodeling. This review summarizes recent insights into the mechanisms by which adaptive and innate immune signals participate in the transition of cardiac fibroblasts to activated myofibroblasts and highlights the existing gaps of knowledge as relates to the development of right ventricular fibrosis.

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3Δ25bp variant.

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3Δ25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3Δ25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3Δ25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3Δ25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.

Computational design and in vitro characterization of an integrated maglev pump-oxygenator.

For the need for respiratory support for patients with acute or chronic lung diseases to be addressed, a novel integrated maglev pump-oxygenator (IMPO) is being developed as a respiratory assist device. IMPO was conceptualized to combine a magnetically levitated pump/rotor with uniquely configured hollow fiber membranes to create an assembly-free, ultracompact system. IMPO is a self-contained blood pump and oxygenator assembly to enable rapid deployment for patients requiring respiratory support or circulatory support. In this study, computational fluid dynamics (CFD) and computer-aided design were conducted to design and optimize the hemodynamics, gas transfer, and hemocompatibility performances of this novel device. In parallel, in vitro experiments including hydrodynamic, gas transfer, and hemolysis measurements were conducted to evaluate the performance of IMPO. Computational results from CFD analysis were compared with experimental data collected from in vitro evaluation of the IMPO. The CFD simulation demonstrated a well-behaved and streamlined flow field in the main components of this device. The results of hydrodynamic performance, oxygen transfer, and hemolysis predicted by computational simulation, along with the in vitro experimental data, indicate that this pump-lung device can provide the total respiratory need of an adult with lung failure, with a low hemolysis rate at the targeted operating condition. These detailed CFD designs and analyses can provide valuable guidance for further optimization of this IMPO for long-term use.

Functional and biocompatibility performances of an integrated Maglev pump-oxygenator.

To provide respiratory support for patients with lung failure, a novel compact integrated pump-oxygenator is being developed. The functional and biocompatibility performances of this device are presented. The pump-oxygenator is designed by combining a magnetically levitated pump/rotor with a uniquely configured hollow fiber membrane bundle to create an assembly free, ultracompact, all-in-one system. The hemodynamics, gas transfer and biocompatibility performances of this novel device were investigated both in vitro in a circulatory flow loop and in vivo in an ovine animal model. The in vitro results showed that the device was able to pump blood flow from 2 to 8 L/min against a wide range of pressures and to deliver an oxygen transfer rate more than 300 mL/min at a blood flow of 6 L/min. Blood damage tests demonstrated low hemolysis (normalized index of hemolysis [NIH] approximately 0.04) at a flow rate of 5 L/min against a 100-mm Hg afterload. The data from five animal experiments (4 h to 7 days) demonstrated that the device could bring the venous blood to near fully oxygen-saturated condition (98.6% +/- 1.3%). The highest oxygen transfer rate reached 386 mL/min. The gas transfer performance was stable over the study duration for three 7-day animals. There was no indication of blood damage. The plasma free hemoglobin and platelet count were within the normal ranges. No gross thrombus is found on the explanted pump components and fiber surfaces. Both in vitro and in vivo results demonstrated that the newly developed pump-oxygenator can achieve sufficient blood flow and oxygen transfer with excellent biocompatibility.

Multiscale structural analysis of mouse lingual myoarchitecture employing diffusion spectrum magnetic resonance imaging and multiphoton microscopy.

The tongue consists of a complex, multiscale array of myofibers that comprise the anatomical underpinning of lingual mechanical function. 3-D myoarchitecture was imaged in mouse tongues with diffusion spectrum magnetic resonance imaging (DSI) at 9.4 T (b(max) 7000 smm, 150-microm isotropic voxels), a method that derives the preferential diffusion of water/voxel, and high-throughput (10 fps) two-photon microscope (TPM). Net fiber alignment was represented for each method in terms of the local maxima of an orientational distribution function (ODF) derived from the local diffusion (DSI) and 3-D structural autocorrelation (TPM), respectively. Mesoscale myofiber tracts were generated by alignment of the principal orientation vectors of the ODFs. These data revealed a consistent relationship between the properties of the respective ODFs and the virtual superimposition of the distributed mesoscale myofiber tracts. The identification of a mesoscale anatomical construct, which specifically links the microscopic and macroscopic spatial scales, provides a method for relating the orientation and distribution of cells and subcellular components with overall tissue morphology, thus contributing to the development of multiscale methods for mechanical analysis.

Associating the mesoscale fiber organization of the tongue with local strain rate during swallowing.

The tongue is an intricately configured muscular organ that undergoes a stereotypical set of deformations during the course of normal human swallowing. In order to demonstrate quantitatively the relationship between 3D aligned lingual fiber organization and mechanics during swallowing, the tissue's myoarchitecture and strain rate were imaged before and during the propulsive phase of a 3.0ml water bolus swallow. Mesoscale fiber organization was imaged with high-resolution diffusion tensor imaging (DTI) and multi-voxel myofiber tracts generated along maximum diffusion vectors. Tissue compression/expansion was obtained via lingual pressure-gated phase-contrast (PC) MRI, a method which determines local strain rate as a function of the phase shift occurring along an applied gradient vector. The co-alignment of myofiber tract direction and the localized principal strain rate vectors was obtained by translating the strain rate tensor into the reference frame with the primary axis parallel to the maximum diffusion vector using Mohr's circle, resulting in the generation of fiber-aligned strain rate (FASR). DTI tractography displayed the complete fiber anatomy of the tongue, consisting of a core region of orthogonally aligned fibers encased within a longitudinal sheath, which merge with the externally connected styloglossus, hyoglossus, and genioglossus fibers. FASR images obtained in the mid-sagittal plane demonstrated that bolus propulsion was associated with prominent compressive strain aligned with the genioglossus muscle combined with expansive strain aligned with the verticalis and geniohyoid muscles. These data demonstrate that lingual deformation during swallowing involves complex interactions involving intrinsic and extrinsic muscles, whose contractility is directed by the alignment of mesoscale fiber tracts.