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ObjectiveThe 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 resultsPigs 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.ConclusionSignificant 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.

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.

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.

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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 ultrasoundenhanced 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 0.4 ± 0.2 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 2.4 ± 0.7 mm to 1.8 ± 0.6 mm in the single array case. The distance is further reduced to 0.4 ± 0.2 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 ultrasoundenhanced drug delivery in vivo.

Chronic low back pain causes more disability worldwide than any other condition, and is thought to arise in part through loss of biomechanical function of degenerate intervertebral discs (IVD). Current treatments can involve replacing part or all of the degenerate IVD by invasive surgery. Our vision is to develop a minimally invasive approach in which high intensity focused ultrasound (HIFU) is used to mechanically fractionating degenerate tissue in an IVD; a fine needle is then used to first remove the fractionated tissue and then inject a biomaterial able to restore normal physiological function. The goal of this manuscript is to demonstrate the feasibility of trans-spinal HIFU delivery using simulations of three-dimensional ultrasound propagation in models derived from patient CT scans. The CT data were segmented in to bone, fat and other soft tissue for three patients. Ultrasound arrays were placed around the waist of each patient model and time-reversal was used to determine the source signals necessary to create a focus in the centre of the disc. The simulations showed that for 0.5 MHz ultrasound a focus could be created in most of the lumbar IVDs, with the pressure focal gain ranging from 3.2 to 13.7. In conclusion, it is shown that, with patient specific planning, focusing ultrasound into an IVD is possible in the majority of cases despite the complex acoustic path introduced by the bony structures of the spine.