Complete spatiotemporal quantification of cardiac motion in mice through enhanced acquisition and super-resolution reconstruction.

The quantification of cardiac motion using cardiac magnetic resonance imaging (CMR) has shown promise as an early-stage marker for cardiovascular diseases. Despite the growing popularity of CMR-based myocardial strain calculations, measures of complete spatiotemporal strains (i.e., three-dimensional strains over the cardiac cycle) remain elusive. Complete spatiotemporal strain calculations are primarily hampered by poor spatial resolution, with the rapid motion of the cardiac wall also challenging the reproducibility of such strains. We hypothesize that a super-resolution reconstruction (SRR) framework that leverages combined image acquisitions at multiple orientations will enhance the reproducibility of complete spatiotemporal strain estimation. Two sets of CMR acquisitions were obtained for five wild-type mice, combining short-axis scans with radial and orthogonal long-axis scans. Super-resolution reconstruction, integrated with tissue classification, was performed to generate full four-dimensional (4D) images. The resulting enhanced and full 4D images enabled complete quantification of the motion in terms of 4D myocardial strains. Additionally, the effects of SRR in improving accurate strain measurements were evaluated using an in-silico heart phantom. The SRR framework revealed near isotropic spatial resolution, high structural similarity, and minimal loss of contrast, which led to overall improvements in strain accuracy. In essence, a comprehensive methodology was generated to quantify complete and reproducible myocardial deformation, aiding in the much-needed standardization of complete spatiotemporal strain calculations.

Disrupted Stiffness Ratio Alters Nuclear Mechanosensing.

The ability of endothelial cells to sense and respond to dynamic changes in blood flow is critical for vascular homeostasis and cardiovascular health. The mechanical and geometric properties of the nuclear and cytoplasmic compartments affect mechanotransduction. We hypothesized that alterations to these parameters have resulting mechanosensory consequences. Using atomic force microscopy and mathematical modeling, we assessed how the nuclear and cytoplasmic compartment stiffnesses modulate shear stress transfer to the nucleus within aging endothelial cells. Our computational studies revealed that the critical parameter controlling shear transfer is not the individual mechanics of these compartments, but the stiffness ratio between them. Replicatively aged cells had a reduced stiffness ratio, attenuating shear transfer, while the ratio was not altered in a genetic model of accelerated aging. We provide a theoretical framework suggesting that dysregulation of the shear stress response can be uniquely imparted by relative mechanical changes in subcellular compartments.

On the possibility of estimating myocardial fiber architecture from cardiac strains.

The myocardium is composed of a complex network of contractile myofibers that are organized in such a way as to produce efficient contraction and relaxation of the heart. The myofiber architecture in the myocardium is a key determinant of cardiac motion and the global or organ-level function of the heart. Reports of architectural remodeling in cardiac diseases, such as pulmonary hypertension and myocardial infarction, potentially contributing to cardiac dysfunction call for the inclusion of an architectural marker for an improved assessment of cardiac function. However, the in-vivo quantification of three-dimensional myo-architecture has proven challenging. In this work, we examine the sensitivity of cardiac strains to varying myofiber orientation using a multiscale finite-element model of the LV. Additionally, we present an inverse modeling approach to predict the myocardium fiber structure from cardiac strains. Our results indicate a strong correlation between fiber orientation and LV kinematics, corroborating that the fiber structure is a principal determinant of LV contractile behavior. Our inverse model was capable of accurately predicting the myocardial fiber range and regional fiber angles from strain measures. A concrete understanding of the link between LV myofiber structure and motion, and the development of non-invasive and feasible means of characterizing the myocardium architecture is expected to lead to advanced LV functional metrics and improved prognostic assessment of structural heart disease.

Liquid Drug Delivery Approaches for the Treatment of Occlusive Arterial Disease: A Systematic Review.

OBJECTIVE: Local Liquid drug (LLD) delivery devices have recently emerged as a novel approach to treat peripheral arterial disease. This systemic review aims to identify and evaluate the clinical utility of the most commonly used delivery devices. METHODS: A systemic review was performed using the Medical Subjects Heading terms of "drug delivery," "liquid," "local," and "cardiovascular disease" in PubMed, Google Scholar, and Scopus. RESULTS: Four commonly used delivery devices were identified, including (1) the Bullfrog Micro-Infusion Device, (2) the ClearWay RX Catheter, (3) the Occlusion Perfusion Catheter, and (4) the Targeted Adjustable Pharmaceutical Administration. All have shown to successfully deliver liquid therapeutic into the target lesion and have exhibited favorable safety and efficacy profiles in preclinical and clinical trials. The LLD devices have the ability to treat very long or multiple lesions with a single device, providing a more economical option. The safety profile in LLD clinical studies is also favorable in view of recent concerns regarding adverse events with crystalline-paclitaxel-coated devices. CONCLUSION: There is clear clinical evidence to support the concept of local liquid delivery to treat occlusive arterial disease. CLINICAL IMPACT: The 'leave nothing behind' strategy has been at the forefront of the most recent innovations in the field of interventional cardiology and vascular interventions. Although drug coated balloons have overcome limitations associated with plain old balloon angioplasty and peripheral stents, recent safety concerns and cost considerations have impacted their usage. In this review, various liquid drug delivery devices are presented, showcasing their capabilities and success in both preclinical and clinical settings. These innovative liquid delivery devices, capable of targeted delivery and their ability to be re-used for multiple treatment sites, may provide solutions for current unmet clinical needs.

Precision delivery of liquid therapy into the arterial wall for the treatment of peripheral arterial disease.

Perfusion catheters have recently emerged as a novel approach to deliver liquid anti-proliferative agents into flow obstructed arterial segments. The purpose of this study was to determine the impact of luminal delivery pressure on liquid drug penetration into the vessel wall. An ex vivo model using harvested porcine carotid arteries and a two-dimensional computational model were utilized to determine the impact of delivery pressure of liquid therapy into the arterial wall. A pig peripheral injury model determined the impact of intra-luminal delivery pressure on drug retention. Ex vivo results demonstrated that depth of fluid penetration varies from 6.93 ± 1.90% at 0 atm to 27.75 ± 6.61% penetration of the medial layer at 0.4 atm. Computational results had similar outcomes, as penetration varied between 4.4% and 22.84%. The in vivo results demonstrated significant increase in drug delivery to the arterial tissue at 0.4 atm versus 0.1 atm at 1 h (23.43 ± 13.59 ng/mg vs. 2.49 ± 1.81 ng/mg, p = 0.026) and 7 days (0.50 ± 0.39 ng/mg vs. 0.018 ± 0.023 ng/mg, p = 0.0496). The result of this study provides an innovative strategic and technical approach to enable targeted liquid therapy.

Machine-Learning based model order reduction of a biomechanical model of the human tongue.

BACKGROUND AND OBJECTIVES: This paper presents the results of a Machine-Learning based Model Order Reduction (MOR) method applied to a complex 3D Finite Element (FE) biomechanical model of the human tongue, in order to create a Digital Twin Model (DTM) that enables real-time simulations. The DTM is designed for future inclusion in a computer assisted protocol for tongue surgery planning. METHODS: The proposed method uses an "a posteriori" MOR that allows, from a limited number of simulations with the FE model, to predict in real time mechanical responses of the human tongue to muscle activations. RESULTS: The MOR method is evaluated for simulations associated with separate single tongue muscle activations. It is shown to be able to account with a sub-millimetric spatial accuracy for the non-linear dynamical behavior of the tongue model observed in these simulations. CONCLUSION: Further evaluations of the MOR method will include tongue movements induced by multiple muscle activations. At this stage our MOR method offers promising perspectives for the use of the tongue model in a clinical context to predict the impact of tongue surgery on tongue mobility. As a long term application, this DTM of the tongue could be used to predict the functional consequences of the surgery in terms of speech production and swallowing.

In vivo estimation of normal left ventricular stiffness and contractility based on routine cine MR acquisition.

Post-myocardial infarction remodeling process is known to alter the mechanical properties of the heart. Biomechanical parameters, such as tissue stiffness and contractility, would be useful for clinicians to better assess the severity of the diseased heart. However, these parameters are difficult to obtain in the current clinical practice. In this paper, we estimated subject-specific in vivo myocardial stiffness and contractility from 21 healthy volunteers, based on left ventricle models constructed from data acquired from routine cardiac MR acquisition only. The subject-specific biomechanical parameters were quantified using an inverse finite-element modelling approach. The personalized models were evaluated against relevant clinical metrics extracted from the MR data, such as circumferential strain, wall thickness and fractional thickening. We obtained the ranges of healthy biomechanical indices of 1.60 ± 0.22 kPa for left ventricular stiffness and 95.13 ± 14.56 kPa for left ventricular contractility. These reference normal values can be used for future model-based investigation on the stiffness and contractility of ischemic myocardium.

Influence of Collaterals on True FFR Prediction for a Left Main Stenosis with Concomitant Lesions: An In Vitro Study.

With the aim of assisting interventional cardiologists during decision making for revascularization, reduced-order (0D) approaches have been developed to predict the true fractional flow reserve (FFRTrue) of individual stenoses in multiple-lesion arrangements. In this study, a general equation was derived to predict the FFRTrue of a left main (LM) coronary stenosis with downstream lesions, one in the left anterior descending (LAD) and the other in the left circumflex (LCx) artery, and distinct collateral circulations supplying each daughter artery. An in vitro model mimicking the fractal nature of LM bifurcation trees with collateral branches was developed to validate the FFR values obtained with the prediction model (FFR Pred Model ). Our results demonstrated that: (1) considering collaterals significantly improved the FFR Pred Model estimation for a moderate LM stenosis with two downstream lesions as compared to computations with no collateral consideration (p < 0.001): mean absolute error |FFR Pred Model - FFRTrue| ± SD was equal to 0.02 ± 0.01 vs. 0.04 ± 0.02 respectively, and (2) Deviations from FFRTrue for LM stenoses are correlated to both, downstream lesion severities and collateral developments. The present study supports the hypothesis that collateral circulations supplying the LAD and LCx must be considered when predicting the FFRTrue of an LM stenosis with downstream lesions.

Intraluminal Ultrasonic Palpation Imaging Technique Revisited for Anisotropic Characterization of Healthy and Atherosclerotic Coronary Arteries: A Feasibility Study.

Accurate mechanical characterization of coronary atherosclerotic lesions remains essential for the in vivo detection of vulnerable plaques. Using intravascular ultrasound strain measurements and based on the mechanical response of a circular and concentric vascular model, E. I. Céspedes, C. L. de Korte and A. F. van der Steen developed an elasticity-palpography technique in 2000 to estimate the apparent stress-strain modulus palpogram of the thick subendoluminal arterial wall layer. More recently, this approach was improved by our group to consider the real anatomic shape of the vulnerable plaque. Even though these two studies highlighted original and promising approaches for improving the detection of vulnerable plaques, they did not overcome a main limitation related to the anisotropic mechanical behavior of the vascular tissue. The present study was therefore designed to extend these previous approaches by considering the orthotropic mechanical properties of the arterial wall and lesion constituents. Based on the continuum mechanics theory prescribing the strain field, an elastic anisotropy index was defined. This new anisotropic elasticity-palpography technique was successfully applied to characterize ten coronary plaque and one healthy vessel geometries of patients imaged in vivo with intravascular ultrasound. The results revealed that the anisotropy index-palpograms were estimated with a good accuracy (with a mean relative error of 26.8 ± 48.8%) compared with ground true solutions.

Noninvasive Vascular Modulography Method for Imaging the Local Elasticity of Atherosclerotic Plaques: Simulation and In Vitro Vessel Phantom Study.

Mechanical and morphological characterization of atherosclerotic lesions in carotid arteries remains an essential step for the evaluation of rupture prone plaques and the prevention of strokes. In this paper, we propose a noninvasive vascular imaging modulography (NIV-iMod) method, which is capable of reconstructing a heterogeneous Young's modulus distribution of a carotid plaque from the Von Mises strain elastogram. Elastograms were computed with noninvasive ultrasound images using the Lagrangian speckle model estimator and a dynamic segmentation-optimization procedure to highlight mechanical heterogeneities. This methodology, based on continuum mechanics, was validated in silico with finite-element model strain fields and ultrasound simulations, and in vitro with polyvinyl alcohol cryogel phantoms based on magnetic resonance imaging geometries of carotid plaques. In silico, our results show that the NiV-iMod method: 1) successfully detected and quantified necrotic core inclusions with high positive predictive value (PPV) and sensitivity value (SV) of 81±10% and 91±6%; 2) quantified Young's moduli of necrotic cores, fibrous tissues, and calcium inclusions with mean values of 32±23, 515±30, and 3160±218 kPa (ground true values are 10, 600, and 5000 kPa); and 3) overestimated the cap thickness by . In vitro, the PPV and SV for detecting soft inclusions were 60±21% and 88±9%, and Young's modulus mean values of mimicking lipid, fibrosis, and calcium were 34±19, 193±14, and 649±118 kPa (ground true values are 25±3, 182±21, and 757±87 kPa).

Principal Strain Vascular Elastography: Simulation and Preliminary Clinical Evaluation.

It is difficult to produce reliable polar strain elastograms (radial and circumferential) because the center of the carotid artery is typically unknown. Principal strain imaging can overcome this limitation, but suboptimal lateral displacement estimates make this an impractical approach for visualizing mechanical properties within the carotid artery. We hypothesized that compounded plane wave imaging can minimize this problem. To test this hypothesis, we performed (i) simulations with vessels of varying morphology and mechanical behavior (i.e., isotropic and transversely isotropic), and (ii) a pilot study with 10 healthy volunteers. The accuracy of principal and polar strain (computed using knowledge of the precise vessel center) elastograms varied between 7% and 17%. In both types of elastograms, strain concentrated at the junction between the fibrous cap and the vessel wall, and the strain magnitude decreased with increasing fibrous cap thickness. Elastograms of healthy volunteers were consistent with those of transversely isotropic homogeneous vessels; they were spatially asymmetric, a trend that was common to both principal and polar strains. No significant differences were observed in the mean strain recovered from principal and polar strains (p > 0.05). This investigation indicates that principal strain elastograms measured with compounding plane wave imaging overcome the problems incurred when polar strain elastograms are computed with imprecise estimates of the vessel center.

Sequential Proximal Optimizing Technique in Provisional Bifurcation Stenting With Everolimus-Eluting Bioresorbable Vascular Scaffold: Fractal Coronary Bifurcation Bench for Comparative Test Between Absorb and XIENCE Xpedition.

OBJECTIVES: The aim of this fractal bifurcation bench study was to compare provisional bifurcation stenting with a "re-POT" sequence, comprising a proximal optimizing technique (POT), side branch inflation, and final POT, between a bioresorbable vascular scaffold (BVS) and a metallic stent. BACKGROUND: Re-POT proved significantly better than kissing balloon inflation in maintaining circular geometry without overstretch in metal stents, while significantly reducing side branch ostium strut obstruction and global strut malapposition. This should be useful for BVSs, which are more easily breakable. METHODS: Twenty left main-like and 20 left anterior descending-like fractal coronary bifurcation bench models used 10 each 2.5 × 24 mm and 3.5 × 24 mm Absorb (Ab) BVSs and 10 each 2.5 × 24 mm and 3.5 × 24 mm XIENCE Xpedition (XX) metal stents, implanted by re-POT, with optical coherence tomographic analysis at each step and micro-computed tomographic analysis of Ab devices to detect strut fracture. RESULTS: With Ab devices, re-POT reduced percentage strut malapposition close to XX rates (0.8 ± 0.7% vs. 0.0 ± 0.0%, p < 0.05; 3.5 ± 1.7% vs. 0.3 ± 0.6%, p < 0.05), conserving proximal circularity (elliptical ratio, 1.04 vs. 1.03 and 1.04 vs. 1.04; p = NS). Mean post-re-POT proximal expansion was 0.6 ± 0.1 mm (+21.6 ± 2.1%) for 2.5-mm and 1.0 ± 0.1 mm (+23.6 ± 2.2%) for 3.5-mm Ab devices, with only 1 strut fracture (left anterior descending-like bench). Side branch ostium strut obstruction was greater with Ab scaffolds than XX stents: 41.1 ± 9.4% versus 16.4 ± 8.1% (p < 0.05) and 31.8 ± 3.2% versus 10.0 ± 5.3% (p < 0.05), respectively, for 2.5- and 3.5-mm scaffolds and stents. Ab scaffolds showed 2 ± 1% moderate but significant late recoil as of 1 h, reaching 4 ± 2% by 24 h (p < 0.05). CONCLUSIONS: Re-POT optimized most Ab provisional bifurcation treatments, without fracture, respecting fractal geometry, and without exceeding 1.0-mm proximal differential diameter.

The Imaging Modulography Technique Revisited for High-Definition Intravascular Ultrasound: Theoretical Framework.

Mechanical characterization of atherosclerotic lesions remains an essential step for the detection of vulnerable plaques (VPs). Recently, an intravascular ultrasound (IVUS) elasticity reconstruction method (iMOD) has been tested in vivo by our group. The major limitation of iMOD is the need to estimate the strain field in the entire VP despite attenuated depth penetration signals when using high-definition (HD) IVUS systems. Therefore, an extended iMOD approach (E-iMOD) was designed and applied to coronary lesions of patients imaged in vivo with IVUS. The E-iMOD method (i) quantified necrotic core areas with a mean absolute relative error of 3.5 ± 3.5% and (ii) identified Young's moduli of the necrotic cores and fibrous regions with mean values of 5.7 ± 0.8 kPa and 794.5 ± 22.0 kPa instead of 5 kPa and 800 kPa, respectively. This study demonstrates the potential of the improved HD-IVUS modulography technique E-iMOD to characterize coronary VPs.

Noninvasive Vascular Elastography With Plane Strain Incompressibility Assumption Using Ultrafast Coherent Compound Plane Wave Imaging.

Plane strain tensor estimation using non-invasive vascular ultrasound elastography (NIVE) can be difficult to achieve using conventional focus beamforming due to limited lateral resolution and frame rate. Recent developments in compound plane wave (CPW) imaging have led to high speed and high resolution imaging. In this study, we present the performance of NIVE using coherent CPW. We show the impact of CPW beamforming on strain estimates compared to conventional focus sequences. To overcome the inherent variability of lateral strains, associated with the low lateral resolution of linear array transducers, we use the plane strain incompressibility to constrain the estimator. Taking advantage of the approximate tenfold increase in frame rate of CPW compared with conventional focus imaging, we introduce a time-ensemble estimation approach to further improve the elastogram quality. By combining CPW imaging with the constrained Lagrangian speckle model estimator, we observe an increase in elastography quality (∼ 10 dB both in signal-to-noise and contrast-to-noise ratios) over a wide range of applied strains (0.02 to 3.2%).

Comparative Analysis of Sequential Proximal Optimizing Technique Versus Kissing Balloon Inflation Technique in Provisional Bifurcation Stenting: Fractal Coronary Bifurcation Bench Test.

OBJECTIVES: This study used a fractal bifurcation bench model to compare 6 optimization sequences for coronary bifurcation provisional stenting, including 1 novel sequence without kissing balloon inflation (KBI), comprising initial proximal optimizing technique (POT) + side-branch inflation (SBI) + final POT, called "re-POT." BACKGROUND: In provisional bifurcation stenting, KBI fails to improve the rate of major adverse cardiac events. Proximal geometric deformation increases the rate of in-stent restenosis and target lesion revascularization. METHODS: A bifurcation bench model was used to compare KBI alone, KBI after POT, KBI with asymmetric inflation pressure after POT, and 2 sequences without KBI: initial POT plus SBI, and initial POT plus SBI with final POT (called "re-POT"). For each protocol, 5 stents were tested using 2 different drug-eluting stent designs: that is, a total of 60 tests. RESULTS: Compared with the classic KBI-only sequence and those associating POT with modified KBI, the re-POT sequence gave significantly (p < 0.05) better geometric results: it reduced SB ostium stent-strut obstruction from 23.2 ± 6.0% to 5.6 ± 8.3%, provided perfect proximal stent apposition with almost perfect circularity (ellipticity index reduced from 1.23 ± 0.02 to 1.04 ± 0.01), reduced proximal area overstretch from 24.2 ± 7.6% to 8.0 ± 0.4%, and reduced global strut malapposition from 40 ± 6.2% to 2.6 ± 1.4%. CONCLUSIONS: In comparison with 5 other techniques, the re-POT sequence significantly optimized the final result of provisional coronary bifurcation stenting, maintaining circular geometry while significantly reducing SB ostium strut obstruction and global strut malapposition. These experimental findings confirm that provisional stenting may be optimized more effectively without KBI using re-POT.

Coronary artery atherectomy reduces plaque shear strains: an endovascular elastography imaging study.

Mechanical response and properties of the arterial wall can be used to identify the biomechanical instability of plaques and predict their vulnerability to rupture. Shear strain elastography (SSE) is proposed to identify vulnerable plaque features attributed to mechanical structural heterogeneities. The aims of this study were: 1) to report on the potential of SSE to identify atherosclerotic plaques; and 2) to use SSE maps to highlight biomechanical changes in lesion characteristics after directional coronary atherectomy (DCA) interventions. For this purpose, SSE was imaged using in vivo intravascular ultrasound (IVUS) radio-frequency data collected from 12 atherosclerotic patients before and after DCA intervention. Coronary atherosclerotic plaques (pre-DCA) showed high SSE magnitudes with large affected areas. There were good correlations between SSE levels and soft plaque content (i.e., cellular fibrosis, thrombosis and fibrin) (mean |SSE| vs. soft plaque content: r = 0.82, p < 0.01). Significant differences were noticed between SSE images before and after DCA. Stable arteries (post-DCA) exhibited lower values than pre-DCA vessels (e.g., pre-DCA: mean |SSE| = 3.9 ± 0.2% vs. 1.1 ± 0.2% post-DCA, p < 0.001). Furthermore, SSE magnitude was statistically higher in plaques with a high level of inflammation (e.g., mean |SSE| had values of 4.8 ± 0.4% in plaques with high inflammation, whereas it was reduced to 1.8 ± 0.2% with no inflammation, p < 0.01). This study demonstrates the potential of the IVUS-based SSE technique to detect vulnerable plaques in vivo.

Endovascular shear strain elastography for the detection and characterization of the severity of atherosclerotic plaques: in vitro validation and in vivo evaluation.

This work explores the potential of shear strain elastograms to identify vulnerable atherosclerotic plaques. The Lagrangian speckle model estimator (LSME) elasticity imaging method was further developed to estimate shear strain elasticity (SSE). Three polyvinyl alcohol cryogel vessel phantoms were imaged with an intravascular ultrasound (IVUS) scanner. The estimated SSE maps were validated against finite-element results. Atherosclerosis was induced in carotid arteries of eight Sinclair mini-pigs using a combination of surgical techniques, diabetes and a high-fat diet. IVUS images were acquired in vivo in 14 plaques before euthanasia and histology. All plaques were characterized by high magnitudes in SSE maps that correlated with American Heart Association atherosclerosis stage classifications (r = 0.97, p < 0.001): the worse the plaque condition the higher was the absolute value of SSE, i.e. |SSE| (e.g., mean |SSE| was 3.70 ± 0.40% in Type V plaques, whereas it was reduced to 0.11 ± 0.01% in normal walls). This study indicates the feasibility of using SSE to highlight atherosclerotic plaque vulnerability characteristics.

Effects of mechanical properties and atherosclerotic artery size on biomechanical plaque disruption - mouse vs. human.

Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic apoE(-/-) mice, in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero-stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE(-/-) mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans.