3D ultrafast ultrasound imaging in vivo

Very high frame rate ultrasound imaging has recently allowed for the extension of the applications of echography to new fields of study such as the functional imaging of the brain, cardiac electrophysiology, and the quantitative imaging of the intrinsic mechanical properties of tumors, to name a few, non-invasively and in real time. In this study, we present the first implementation of Ultrafast Ultrasound Imaging in 3D based on the use of either diverging or plane waves emanating from a sparse virtual array located behind the probe. It achieves high contrast and resolution while maintaining imaging rates of thousands of volumes per second. A customized portable ultrasound system was developed to sample 1024 independent channels and to drive a 32 x 32 matrix-array probe. Its ability to track in 3D transient phenomena occurring in the millisecond range within a single ultrafast acquisition was demonstrated for 3D Shear-Wave Imaging, 3D Ultrafast Doppler Imaging, and, finally, 3D Ultrafast combined Tissue and Flow Doppler Imaging. The propagation of shear waves was tracked in a phantom and used to characterize its stiffness. 3D Ultrafast Doppler was used to obtain 3D maps of Pulsed Doppler, Color Doppler, and Power Doppler quantities in a single acquisition and revealed, at thousands of volumes per second, the complex 3D flow patterns occurring in the ventricles of the human heart during an entire cardiac cycle, as well as the 3D in vivo interaction of blood flow and wall motion during the pulse wave in the carotid at the bifurcation. This study demonstrates the potential of 3D Ultrafast Ultrasound Imaging for the 3D mapping of stiffness, tissue motion, and flow in humans in vivo and promises new clinical applications of ultrasound with reduced intra--and inter-observer variability

Electromechanical Wave Imaging

Cardiac conduction abnormalities and arrhythmias are associated with stroke, heart failure, and sudden cardiac death, and remain a major cause of death and disability. However, the imaging tools currently available to the physician to guide these treatments by mapping the activation sequence of the heart are invasive, ionizing, time-consuming, and costly. In this dissertation, Electromechanical Wave Imaging (EWI) is described with an aim to characterize normal and abnormal rhythms noninvasively, transmurally, at the point of care, and in real time. More specifically, the methods to map the electromechanical wave (EW), i.e., the transient deformations occurring in response to the electrical activation of the heart, are developed and optimized. The correlation between EW and the electrical activation sequence during both normal and abnormal rhythms is demonstrated in canines in vivo and in silico. Finally, EWI is shown to noninvasively detect and characterize arrhythmias and conduction disorders in humans. Novel ultrasound imaging methodologies were developed to track the EW. Radio-frequency (RF) frames acquired at high frame rates were used in conjunction with cross-correlation algorithms to map the onset of the small, localized, transient deformations resulting from the electrical activation and forming the EW. To validate the capability of the EW to characterize cardiac rhythm, it was compared against the electrical activation in vivo and in silico. A high correlation between the electrical and electromechanical activations was obtained in normal canines in vivo during various pacing schemes and sinus rhythm. An in vivo-in silico framework was also developed to demonstrate that this correlation is maintained transmurally and independently of the imaging angle. EWI was also validated in abnormal canine hearts in vivo during ischemia, left bundle branch block, or atrio-ventricular dissociation. In a clinical feasibility study, we demonstrated that EWI was capable of noninvasively mapping normal and abnormal activation patterns in all four cardiac chambers of human subjects using a readily available clinical ultrasound scanner. Specifically, EWI maps were generated for three heart failure patients with cardiac resynchronization therapy (CRT) devices and for three patients with atrial flutter who subsequently underwent catheter mapping and radiofrequency ablation. Preliminary validation of EWI maps against invasive transcutaneous electroanatomical cardiac mapping was also demonstrated. EWI has the potential of becoming a noninvasive and highly translational technology that can serve as a unique imaging tool for the early detection, diagnosis and treatment monitoring and follow-up of arrhythmias and conduction disorders through ultrasound-based mapping of the transmural electromechanical activation sequence reliably, at the point of care, and in real time

The Effects of Arrhythmogenic Right Ventricular Cardiomyopathy-Causing Proteins on the Mechanical and Signaling Properties of Cardiac Myocytes

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by a high incidence of lethal ventricular arrhythmias, fibrofatty replacement of myocardium, and can account for up to 20% of sudden cardiac death (SCD) cases in the young. Typically involving autosomal dominant transmission, germline mutations in genes encoding desmosomal proteins have been identified as a cause of ARVC, although the pathogenesis of the disease is still unclear. While early detection and treatment can provide a normal life expectancy for the majority of patients, with less than 10% progressing to overt right ventricular failure, low genetic penetrance and epigenetic modifiers (such as endurance exercise) can make the condition difficult to diagnose. Addressing this clinical challenge requires a better understanding of the defective molecular mechanisms that underlie the disease. To that end, the goal of this dissertation is to provide insight into the effects of ARVC-causing mutant proteins on the mechanical and signaling properties of cardiac myocytes. Using elastography and histological techniques, we begin by characterizing the structural and mechanical properties of the native right ventricular myocardium, particularly the right ventricular apex (RVA). Because the RVA is a key site for development of arrhythmias and a potential pacing target, a careful characterization of its structure and mechanical properties are essential for understanding its role in cardiac physiology. In the first section of this dissertation, we perform a systematic analysis of the structural features and mechanical strains in the heart, focusing on the RVA region. More than half of ARVC patients exhibit one or more mutations in genes encoding desmosomal proteins. This has led many investigators to suggest that ARVC is a "disease of the desmosome" in which defective cell-cell adhesion plays a critical pathogenic role, although direct evidence for this hypothesis is lacking. To gain greater insights into potential mechanisms by which desmosomal mutations cause ARVC, we next characterize biomechanical properties and responses to shear stress (motivated by our results in the previous section) in neonatal rat ventricular myocytes expressing two distinct mutant forms of the desmosomal protein plakoglobin which have been linked to ARVC in patients. We show that ARVC-causing mutations in plakoglobin lead to altered cellular distribution of plakoglobin, without alterations in cell mechanical properties or certain early signaling pathways. The identification of defective molecular mechanisms that are common across ARVC-patients remains a strategic area of research. Specifically, recent studies have investigated the mechanistic basis for different ARVC-causing mutations in hopes of identifying common defects in a signaling pathway - information that could be used to develop diagnostic tests or identify therapeutic targets. In the last section of this dissertation, we investigate the effects of mutant plakophilin-2 expression, and repeat key experiments performed in the previous section to identify common defects in mechanical and signaling properties. We identify a common, underlying defect in ARVC pathogenesis. Specifically, we show that disease-causing mutations across different desmosomal proteins can cause the cell to respond abnormally to mechanical shear stress with respect to plakoglobin trafficking

Performance Analysis and Optimization of 2-D Cardiac Strain Imaging for Clinical Applications

Heart disease has remained the deadliest disease in the United States for the past 100 years. Imaging methods are frequently employed in cardiology in order to help clinicians diagnose the specific type of heart disease and to guide treatment decisions. Ultrasound is the most frequently used imaging modality in cardiology because it is inexpensive, portable, easy to use, and extremely safe for patients. Using a variety of imaging processing techniques, deformations exhibited by the cardiac tissue during contraction can be imaged with ultrasound and used as an indicator of myocardial health. This dissertation will demonstrate the clinical implementation of two ultrasound-based strain estimation techniques developed in the Ultrasound and Elasticity Imaging Laboratory at Columbia University. Each of the two imaging methods will be tailored for clinical applications using techniques for optimal strain estimation derived from ultrasound and imaging processing theory. The motion estimation rate (MER) used for strain estimation is examined in the context of the theoretical Strain Filter and used to increase the precision of axial strain estimation. Diverging beam sequences are used to achieve full-view high MER imaging within a single heartbeat. At approximately 500 Hz, the expected elastographic signal-to-noise ratio (E(SNRe|ε)) of the axial strain becomes single-peaked, indicating an absence of “peak-hopping” errors which can severely corrupt strain estimation. In order to mediate the tradeoff in spatial resolution resulting from the use of diverging beams, coherent spatial compounding is used to increase the accuracy of the lateral strain estimation, resulting in a more physiologic strain profile. A sequence with 5 coherently compounded diverging waves is used at 500 Hz to improve the radial SNRe of the strain estimation compared to a single-source diverging sequence at 500 Hz. The first technique, Myocardial Elastography (ME), is used in conjunction with an intracardiac echocardiography (ICE) system to image the formation of thermal ablation lesions in vivo using a canine model (n=6). By comparing the systolic strain before and after the formation of a lesion, lesion maps are generated which allow for the visualization of the lesion in real-time during the procedure. A good correlation is found between the lesion maps and the actual lesion volume as measured using gross pathology (r2=0.86). The transmurality of the lesions are also shown to be in good agreement with gross pathology. Finally, the feasibility of imaging gaps between neighboring lesions is established. Lesion size and the presence of gaps have been associated with the success rate of cardiac ablation procedures, demonstrating the value of ME as a potentially useful technique for clinicians to help improve patient outcomes following ablation procedures. The second technique, Electromechanical Wave Imaging (EWI), is implemented using a transthoracic echocardiography system in a study of heart failure patients (n=16) and healthy subjects (n=4). EWI uses the transient inter-frame strains to generate maps of electromechanical activation, which are then used to distinguish heart failure patients from healthy controls (p<.05). EWI was also shown to be capable of distinguishing responders from non-responders to cardiac resynchronization therapy (CRT) on the basis of the activation time of the lateral wall. These results indicate that EWI could be used as an adjunct tool to monitor patient response to CRT, in addition to helping guide lead placement prior to device implantation

Thérapies ultrasonores cardiaques guidées par élastographie et échographie ultrarapides

Atrial fibrillation (AF) affects 2-3% of the European and North-American population, whereas ventricular tachyarrhythmia (VT) is related to an important risk of sudden death. AF and VT originate from dysfunctional electrical activity in cardiac tissues. Minimally-invasive approaches such as Radio-Frequency Catheter Ablation (RFCA) have revolutionized the treatment of these diseases; however the success rate of RFCA is currently limited by the lack of monitoring techniques to precisely control the extent of thermally ablated tissue.The aim of this thesis is to propose novel ultrasound-based approaches for minimally invasive cardiac ablation under guidance of ultrasound imaging. For this, first, we validated the accuracy and clinical viability of Shear-Wave Elastography (SWE) as a real-time quantitative imaging modality for thermal ablation monitoring in vivo. Second we implemented SWE on an intracardiac transducer and validated the feasibility of evaluating thermal ablation in vitro and in vivo on beating hearts of a large animal model. Third, a dual-mode intracardiac transducer was developed to perform both ultrasound therapy and imaging with the same elements, on the same device. SWE-controlled High-Intensity-Focused-Ultrasound thermal lesions were successfully performed in vivo in the atria and the ventricles of a large animal model. At last, SWE was implemented on a transesophageal ultrasound imaging and therapy device and the feasibility of transesophageal approach was demonstrated in vitro and in vivo. These novel approaches may lead to new clinical devices for a safer and controlled treatment of a wide variety of cardiac arrhythmias and diseases.La fibrillation atriale affecte 2-3% des européens et nord-américains, les tachycardies ventriculaires sont liées à un risque important de mort subite. Les approches minimalement invasives comme l’Ablation par Cathéter Radiofréquence (RFCA) ont révolutionné le traitement de ces maladies, mais le taux de réussite de la RFCA est limité par le manque de techniques d’imagerie pour contrôler cette ablation thermique.Le but de cette thèse est de proposer de nouvelles approches ultrasonores pour des traitements cardiaques minimalement invasifs guidés par échographie.Pour cela nous avons d’abord validé la précision et la viabilité clinique de l’Élastographie par Ondes de Cisaillement (SWE) en tant que modalité d’imagerie quantitative et temps réel pour l’ablation thermique in vivo. Ensuite nous avons implémenté la SWE sur un transducteur intracardiaque et validé la faisabilité d’évaluer l’ablation thermique in vitro et in vivo sur cœur battant de gros animal. Puis nous avons développé un transducteur intracardiaque dual-mode pour effectuer l’ablation et l’imagerie ultrasonores avec les mêmes éléments, sur le même dispositif. Les lésions thermiques induites par Ultrasons Focalisés de Haute Intensité (HIFU) et contrôlées par la SWE ont été réalisées avec succès in vivo dans les oreillettes et les ventricules chez le gros animal. Finalement la SWE a été implémentée sur un dispositif d’imagerie et thérapie ultrasonores transœsophagien et la faisabilité de cette approche a été démontrée in vitro et in vivo. Ces approches originales pourraient conduire à de nouveaux dispositifs cliniques pour des traitements plus sûrs et contrôlés d’un large éventail d’arythmies et maladies cardiaques

Electromechanical wave imaging of normal and ischemic hearts in vivo

Abstract-Electromechanical wave imaging (EWI) has recently been introduced as a noninvasive, ultrasound-based imaging modality, which could map the electrical activation of the heart in various echocardiographic planes in mice, dogs, and humans in vivo. By acquiring radio-frequency (RF) frames at very high frame rates (390-520 Hz), the onset of small, localized, transient deformations resulting from the electrical activation of the heart, i.e., generating the electromechanical wave (EMW), can be mapped. The correlation between the EMW and the electrical activation speed and pacing scheme has previously been reported. In this study, we pursue the development of EWI using both displacements and strains and analysis of the EMW properties in dogs in vivo for early detection of ischemia. EWI was performed in normal and ischemic open-chest dogs during sinus rhythm. Ischemia of increasing severity was obtained by gradually obstructing the left-anterior descending (LAD) coronary artery flow. We also introduce the novel method of motion-matching that achieves the reconstruction of the full EWI ciné-loop at very high frame rates even when the ECG may be irregular or unavailable. Incremental displacements were previously used by our group to map the EMW. This paper focuses on the associated incremental strains, which facilitate the interpretation of the EMW by relating it directly to contraction. Moreover, we define the onset of the EMW as the time, at which the incremental strains change sign after the onset of the QRS complex of the ECG. Based on this definition, isochronal representations of the EMW were generated using a semi-automated method. The isochronal representation of the EMW during sinus rhythm was reproducible and shown similar to electrical activation maps previously reported in the literature. After segmentation using a contour-tracking method, the twoand four-chamber views were imaged and displayed in bi-plane views, allowing a 3-D interpretation of the EMW. EWI was shown to be sensitive to the presence of intermediate ischemia. EWI localized the ischemic region when the LAD flow was obstructed at 60% and beyond and was capable of mapping the increase of the ischemic region size as the LAD occlusion level increased. In conclusion, the activation maps and wave patterns obtained with EWI were similar to the electrical equivalents previously reported in the literature. Moreover, EWI was found to be sensitive enough to detect and map intermediate ischemia. Those that EWI could be used to assess the conduction properties of the myocardium, and detect its ischemic onset and disease progression entirely noninvasively. Index Terms-Electrical mapping, electromechanical wave imaging, high framerate echocardiography, ischemia, radio-frequency speckle-tracking

Electromechanical wave imaging of normal and ischemic hearts in vivo

Electromechanical wave imaging (EWI) has recently been introduced as a noninvasive, ultrasound-based imaging modality, which could map the electrical activation of the heart in various echocardiographic planes in mice, dogs, and humans in vivo. By acquiring radio-frequency (RF) frames at very high frame rates (390520 Hz), the onset of small, localized, transient deformations resulting from the electrical activation of the heart, i.e., generating the electromechanical wave (EMW), can be mapped. The correlation between the EMW and the electrical activation speed and pacing scheme has previously been reported. In this study, we pursue the development of EWI using both displacements and strains and analysis of the EMW properties in dogs in vivo for early detection of ischemia. EWI was performed in normal and ischemic open-chest dogs during sinus rhythm. Ischemia of increasing severity was obtained by gradually obstructing the left-anterior descending (LAD) coronary artery flow. We also introduce the novel method of motion-matching that achieves the reconstruction of the full EWI cin-loop at very high frame rates even when the ECG may be irregular or unavailable. Incremental displacements were previously used by our group to map the EMW. This paper focuses on the associated incremental strains, which facilitate the interpretation of the EMW by relating it directly to contraction. Moreover, we define the onset of the EMW as the time, at which the incremental strains change sign after the onset of the QRS complex of the ECG. Based on this definition, isochronal representations of the EMW were generated using a semi-automated method. The isochronal representation of the EMW during sinus rhythm was reproducible and shown similar to electrical activation maps previously reported in the literature. After segmentation using a contour-tracking method, the two-and four-chamber views were imaged and displayed in bi-plane views, allowing a 3-D interpretation of the EMW. EWI was shown to be sensitive to the presence of intermediate ischemia. EWI localized the ischemic region when the LAD flow was obstructed at 60% and beyond and was capable of mapping the increase of the ischemic region size as the LAD occlusion level increased. In conclusion, the activation maps and wave patterns obtained with EWI were similar to the electrical equivalents previously reported in the literature. Moreover, EWI was found to be sensitive enough to detect and map intermediate ischemia. Those results indicate that EWI could be used to assess the conduction properties of the myocardium, and detect its ischemic onset and disease progression entirely noninvasively. © 2010 IEEE.link_to_subscribed_fulltex