Dual-Array Passive Acoustic Mapping for Cavitation Imaging With Enhanced 2-D Resolution.

Passive acoustic mapping (PAM) techniques have been developed for the purposes of detecting, localizing, and quantifying cavitation activity during therapeutic ultrasound procedures. Implementation with conventional diagnostic ultrasound arrays has allowed planar mapping of bubble acoustic emissions to be overlaid with B-mode anatomical images, with a variety of beamforming approaches providing enhanced resolution at the cost of extended computation times. However, no passive signal processing techniques implemented to date have overcome the fundamental physical limitation of the conventional diagnostic array aperture that results in point spread functions with axial/lateral beamwidth ratios of nearly an order of magnitude. To mitigate this problem, the use of a pair of orthogonally oriented diagnostic arrays was recently proposed, with potential benefits arising from the substantially expanded range of observation angles. This article presents experiments and simulations intended to demonstrate the performance and limitations of the dual-array system concept. The key finding of this study is that source pair resolution of better than 1 mm is now possible in both dimensions of the imaging plane using a pair of 7.5-MHz center frequency conventional arrays at a distance of 7.6cm. With an eye toward accelerating computations for real-time applications, channel count reductions of up to a factor of eight induce negligible performance losses. Modest sensitivities to sound speed and relative array position uncertainties were identified, but if these can be kept on the order of 1% and 1 mm, respectively, then the proposed methods offer the potential for a step improvement in cavitation monitoring capability.

Passive acoustic mapping of extravasation following ultrasound-enhanced drug delivery.

The amount and distribution of chemotherapeutic agents delivered to tumours can vary significantly due to tumour heterogeneity, even under focussed ultrasound (FUS) assisted drug delivery regimes. The ability to non-invasively localise cavitation nuclei of a similar size to therapeutic drugs, both within the vasculature and tumour tissue, may provide a useful marker of ultrasound-enhanced drug delivery and extravasation. Solid polymer based nanoscale cavitation nuclei, under FUS excitation, have previously been shown to extravasate into tissue-mimicking phantoms, and to increase drug delivery in murine tumour models in vivo. Here we show in a tissue-mimicking material that these nuclei, once extravasated under FUS excitation, are still acoustically active and can be non-invasively localised using passive acoustic mapping (PAM). By using a high resolution dual linear array setup in conjunction with adaptive beamformers, we demonstrate that the average 'maximum distance' of a PAM pixel to an extravasated particle across experiments is [Formula: see text] mm. Although the primary objective of the paper is to show that extravascular cavitation can be used as evidence of successful drug extravasation in a tissue-mimicking phantom, we also recognise the physical and computational limitations of using a high resolution dual array setup with adaptive beamformers. Thus as a secondary objective, we evaluate tradeoffs between adaptive and non-adaptive beamformers, as well as between dual and single array geometries. When compared to a conventional beamformer, adaptive beamformers reduce the maximum distance of PAM pixels to extravasated particles from an average of [Formula: see text] mm to [Formula: see text] mm in the single array case. The distance is further reduced to [Formula: see text] mm using the dual array configuration, thereby demonstrating that increasing the solid angle spanned by the PAM array aperture significantly improves drug delivery localisation. Future work will test the applicability of PAM-based monitoring of ultrasound-enhanced drug delivery in vivo.

Arrhythmogenic Remodeling of the Left Ventricle in a Porcine Model of Repaired Tetralogy of Fallot.

BACKGROUND: Ventricular arrhythmias are frequent in patients with repaired tetralogy of Fallot (rTOF), but their origin and underlying mechanisms remain unclear. In this study, the involvement of left ventricular (LV) electrical and structural remodeling was assessed in an animal model mimicking rTOF sequelae. METHODS: Piglets underwent a tetralogy of Fallot repair-like surgery (n=6) or were sham operated (Sham, n=5). Twenty-three weeks post-surgery, cardiac function was assessed in vivo by magnetic resonance imaging. Electrophysiological properties were characterized by optical mapping. LV fibrosis and connexin-43 localization were assessed on histological sections and protein expression assessed by Western Blot. RESULTS: Right ventricular dysfunction was evident, whereas LV function remained unaltered in rTOF pigs. Optical mapping showed longer action potential duration on the rTOF LV epicardium and endocardium. Epicardial conduction velocity was significantly reduced in the longitudinal direction in rTOF LVs but not in the transverse direction compared with Sham. An elevated collagen content was found in LV basal and apical sections from rTOF pigs. Moreover, a trend for connexin-43 lateralization with no change in protein expression was found in the LV of rTOFs. Finally, rTOF LVs had a lower threshold for arrhythmia induction using incremental pacing protocols. CONCLUSIONS: We found an arrhythmogenic substrate with prolonged heterogeneous action potential duration and reduced conduction velocity in the LV of rTOF pigs. This remodeling precedes LV dysfunction and is likely to contribute to ventricular arrhythmias and sudden cardiac death in patients with rTOF.

Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot.

OBJECTIVE: The growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV) structural and electrophysiological remodelling to arrhythmia generation in a preclinical animal model of repaired TOF (rTOF). METHODS AND RESULTS: Pigs mimicking rTOF underwent cardiac MRI functional characterisation and presented with pulmonary regurgitation, RV hypertrophy, dilatation and dysfunction compared with Sham-operated animals (Sham). Optical mapping of rTOF RV-perfused wedges revealed a significant prolongation of RV activation time with slower conduction velocities and regions of conduction slowing well beyond the surgical scar. A reduced protein expression and lateralisation of Connexin-43 were identified in rTOF RVs. A remodelling of extracellular matrix-related gene expression and an increase in collagen content that correlated with prolonged RV activation time were also found in these animals. RV action potential duration (APD) was prolonged in the epicardial anterior region at early and late repolarisation level, thus contributing to a greater APD heterogeneity and to altered transmural and anteroposterior APD gradients in rTOF RVs. APD remodelling involved changes in Kv4.3 and MiRP1 expression. Spontaneous arrhythmias were more frequent in rTOF wedges and more complex in the anterior than in the posterior RV. CONCLUSION: Significant remodelling of RV conduction and repolarisation properties was found in pigs with rTOF. This remodelling generates a proarrhythmic substrate likely to facilitate re-entries and to contribute to sudden cardiac death in patients with rTOF.

Magnetic resonance imaging-compatible circular mapping catheter: an in vivo feasibility and safety study.

AIMS: Interventional cardiac catheter mapping is routinely guided by X-ray fluoroscopy, although radiation exposure remains a significant concern. Feasibility of catheter ablation for common flutter has recently been demonstrated under magnetic resonance imaging (MRI) guidance. The benefit of catheter ablation under MRI could be significant for complex arrhythmias such as atrial fibrillation (AF), but MRI-compatible multi-electrode catheters such as Lasso have not yet been developed. This study aimed at demonstrating the feasibility and safety of using a multi-electrode catheter [magnetic resonance (MR)-compatible Lasso] during MRI for cardiac mapping. We also aimed at measuring the level of interference between MR and electrophysiological (EP) systems. METHODS AND RESULTS: Experiments were performed in vivo in sheep (N = 5) using a multi-electrode, circular, steerable, MR-compatible diagnostic catheter. The most common MRI sequences (1.5T) relevant for cardiac examination were run with the catheter positioned in the right atrium. High-quality electrograms were recorded while imaging with a maximal signal-to-noise ratio (peak-to-peak signal amplitude/peak-to-peak noise amplitude) ranging from 5.8 to 165. Importantly, MRI image quality was unchanged. Artefacts induced by MRI sequences during mapping were demonstrated to be compatible with clinical use. Phantom data demonstrated that this 10-pole circular catheter can be used safely with a maximum of 4°C increase in temperature. CONCLUSIONS: This new MR-compatible 10-pole catheter appears to be safe and effective. Combining MR and multipolar EP in a single session offers the possibility to correlate substrate information (scar, fibrosis) and EP mapping as well as online monitoring of lesion formation and electrical endpoint.

Identification of Region-Specific Myocardial Gene Expression Patterns in a Chronic Swine Model of Repaired Tetralogy of Fallot.

Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery. Two distinct regions (endocardium and epicardium) from both ventricles were analyzed. Expression levels from each localization were compared in order to decipher mechanisms and signaling pathways leading to ventricular dysfunction and arrhythmias in surgically repaired TOF. Several genes were confirmed to participate in ventricular remodeling and cardiac failure and some new candidate genes were described. In particular, these data pointed out FRZB as a heart failure marker. Moreover, calcium handling and contractile function genes (SLN, ACTC1, PLCD4, PLCZ), potential arrhythmia-related genes (MYO5B, KCNA5), and cytoskeleton and cellular organization-related genes (XIRP2, COL8A1, KCNA6) were among the most deregulated genes in rTOF ventricles. To our knowledge, this is the first comprehensive report on global gene expression profiling in the heart of a long-term swine model of repaired TOF.

Magnetic resonance imaging for the exploitation of bubble-enhanced heating by high-intensity focused ultrasound: a feasibility study in ex vivo liver.

Bubble-enhanced heating (BEH) may be exploited to improve the heating efficiency of high-intensity focused ultrasound in liver and to protect tissues located beyond the focal point. The objectives of this study, performed in ex vivo pig liver, were (i) to develop a method to determine the acoustic power threshold for induction of BEH from displacement images measured by magnetic resonance acoustic radiation force imaging (MR-ARFI), and (ii) to compare temperature distribution with MR thermometry for HIFU protocols with and without BEH. The acoustic threshold for generation of BEH was determined in ex vivo pig liver from MR-ARFI calibration curves of local tissue displacement resulting from sonication at different powers. Temperature distributions (MR thermometry) resulting from "conventional" sonications (20 W, 30 s) were compared with those from "composite" sonications performed at identical parameters, but after a HIFU burst pulse (0.5 s, acoustic power over the threshold for induction of BEH). Displacement images (MR-ARFI) were acquired between sonications to measure potential modifications of local tissue displacement associated with modifications of tissue acoustic characteristics induced by the burst HIFU pulse. The acoustic threshold for induction of BEH corresponded to a displacement amplitude of approximately 50 µm in ex vivo liver. The displacement and temperature images of the composite group exhibited a nearly spherical pattern, shifted approximately 4 mm toward the transducer, in contrast to elliptical shapes centered on the natural focal position for the conventional group. The gains in maximum temperature and displacement values were 1.5 and 2, and the full widths at half-maximum of the displacement data were 1.7 and 2.2 times larger than in the conventional group in directions perpendicular to ultrasound propagation axes. Combination of MR-ARFI and MR thermometry for calibration and exploitation of BEH appears to increase the efficiency and safety of HIFU treatment.

Pre-clinical study of in vivo magnetic resonance-guided bubble-enhanced heating in pig liver.

Bubble-enhanced heating (BEH) can be exploited to increase heating efficiency in treatment of liver tumors with non-invasive high-intensity focused ultrasound (HIFU). The objectives of this study were: (i) to demonstrate the feasibility of increasing the heating efficiency of sonication exploiting BEH in pig liver in vivo using a clinical platform; (ii) to determine the acoustic threshold for such effects with real-time, motion-compensated magnetic resonance-guided thermometry; and (iii) to compare the heating patterns and thermal lesion characteristics resulting from continuous sonication and sonication including a burst pulse. The threshold acoustic power for generation of BEH in pig liver in vivo was determined using sonication of 0.5-s duration ("burst pulse") under real-time magnetic resonance thermometry. In a second step, experimental sonication composed of a burst pulse followed by continuous sonication (14.5 s) was compared with conventional sonication (15 s) of identical energy (1.8 kJ). Modification of the heating pattern at the targeted region located at a liver depth between 20 and 25 mm required 600-800 acoustic watts. The experimental group exhibited near-spherical heating with 40% mean enhancement of the maximal temperature rise as compared with the conventional sonication group, a mean shift of 7 ± 3.3 mm toward the transducer and reduction of the post-focal temperature increase. Magnetic resonance thermometry can be exploited to control acoustic BEH in vivo in the liver. By use of experimental sonication, more efficient heating can be achieved while protecting tissues located beyond the focal point.