Title: Toward clinical realization of Myocardial Elastography
Description: Heart disease is the leading cause of death globally. Early diagnosis is the key to successful treatment. By providing noninvasive, non-ionizing, and real-time imaging, echocardiography plays a critical role in identifying heart disease. Compared to other imaging modalities, ultrasound has unparalleled temporal resolution. High frame-rate imaging has enabled the development of new metrics to characterize myocardial mechanics. Strain imaging measures the heart's deformation throughout the cardiac cycle, providing a quantitative assessment of cardiac health. The intention of this dissertation is to bring Myocardial Elastography (ME) closer to clinical realization. ME is a high frame-rate strain imaging technique for transthoracic and intracardiac echocardiography. This work consists of four Aims. There is a fundamental trade-off between spatial and temporal resolution in strain imaging. In Aim 1, the optimal transmit sequence that generates the most accurate and precise strain estimate was determined.

Two common approaches to coherent compounding (full and partial aperture) were compared in simulation and in transthoracic imaging of healthy human subjects (n=5). The optimized subaperture compounding sequence (25-element subperture, 90° angular aperture, 10 virtual sources, 300 Hz frame rate) was compared to the optimized steered compounding sequence (60° angular aperture, 15° tilt, 10 virtual sources, 300 Hz frame rate) and was found to measure strain in healthy human subjects with equivalent precision. The optimal compounding configuration was then evaluated against two other high-frame rate transmit strategies, ECG-gated focused imaging, and wide-beam imaging, in simulation and in healthy subjects (n=7). Achieving the highest level of strain precision, ECG-gated focused imaging was determined to be the preferred imaging approach in patients capable of sustaining a breath hold, with compounding preferred in those unable to do so. Rapid diagnosis is essential to successful treatment of myocardial infarction.

In Aim 2, ME's ability to track infarct formation and recovery, and localize infarct using regional strain measurments, was investigated in a large animal survival model (n=11). Infarcts were generated via ligation of the left anterior descending, imaging regularly for up to 28 days. A radial strain-based metric, percentage of healthy myocardium by strain (PHM_ε), was developed as a marker for healthy myocardial tissue. PHM_ε was strongly linearly correlated with actual infarct size as determined by gross pathology (R2 = 0.80). ME was capable of diagnosing individual myocardial segments as non-infarcted or infarcted with high sensitivity (82%), specificity (92%), and precision (85%) (ROC AUC = 0.90), and tracked infarct recovery from collateral reperfusion through time. Noninvasive strain imaging at rest can improve pre-test probability accuracy, and reduce unnecessary stress testing. In Aim 3, ME's potential to provide early diagnosis of coronary artery disease was investigated in an ongoing study.

Patients undergoing myocardial perfusion imaging were recruited (n=126). Perfusion scores were used as the reference standard. Morphological transformations were integrated into the processing pipeline to reduce variability in the strain measurements. PHM_ε was reintroduced and used to differentiate between patients with and without coronary artery disease. ME was capable of distinguishing between normal patients and those with significant ischemia or infarct (subjects with perfusion defects at rest) with statistical significance (p < 0.05), although a greater sample size is needed to confirm the results. One of the most common treatments for arrhythmia, catheter ablation, can fail if the lesion line intended to terminate the abnormal rhythm is non-contiguous. In Aim 4, the gap resolution and clinical feasibility of Intracardiac Myocardial Elastography (IME) strain imaging, an ablation monitoring technique, was investigated. Lesion size estimation and gap resolution was evaluated in an open chest canine model (n=3), wherein lesion lines consisting of three lesions and two gaps were generated in each canine left ventricle via epicardial ablation.

All gaps were resolvable. Average lesion and gap areas were measured with high agreement (33 ± 14 mm2 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 mm2 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Patients undergoing ablation to treat typical cavotricuspid isthmus atrial flutter (n=5) were imaged throughout the procedure. In all patients, strain decreased in the cavotricuspid isthmus after ablation (mean paired difference of -17 ± 11 %, p < 0.05). Together, these Aims intend to translate a promising imaging method from research to clinical reality.