Strain-based staging classification of left bundle branch block-induced cardiac remodeling predicts reverse remodeling after cardiac resynchronization therapy

Background Left bundle branch block (LBBB)-induced adverse remodeling is a gradual but largely unknown process, causing a variable degree of left ventricular (LV) dysfunction and response to cardiac resynchronization therapy (CRT). In LBBB patients with septal flash (SF), an electro-mechanical continuum of different speckle-tracking strain patterns was observed, with each pattern tightly correlating with the degree of LV remodeling and dysfunction (1) (Figure 1). Purpose In this study, we investigated the relationship between the staged LBBB strain patterns in CRT-eligible patients and their prediction with respect to reverse remodeling and clinical outcome. Methods This study enrolled CRT patients from the PREDICT-CRT study population (2). Inclusion criteria were LV ejection fraction (LVEF) ≤35%, QRS duration ≥120 ms, NYHA class II–IV, absence of right ventricular pacing and availability of speckle tracking strain imaging. All patients underwent an echocardiographic examination before and 12 months after CRT implant. LV volumes, strain and dyssynchrony were assessed. Mid-septal longitudinal strain curves were classified into 5 patterns (LBBB-0 through LBBB-4; Figure 1). Primary endpoint was all-cause mortality. Results The study involved 250 patients (mean age 64±10 years; 79% men) with a mean LVEF of 26±7%. LBBB was present in 220 (89%) patients and 206 (82%) patients had SF. Prior to CRT implant, a LBBB-0 pattern was observed in 33 (13%), LBBB-1 in 33 (13%), LBBB-2 in 39 (16%), LBBB-3 in 44 (18%) and LBBB-4 in 101 (40%) patients. Patients with LBBB-3 and -4 patterns more frequently had LBBB, lower LVEF, increased mechanical dyssynchrony and more prominent SF (p<0.001 for all) compared with patients with LBBB-0, -1 and -2 patterns. Across the stages, CRT resulted in a gradual volumetric response, ranging from no response in stage LBBB-0 patients (ΔLV end-systolic volume +7±33%; ΔLVEF −2±9%) to super-response in stage LBBB-4 patients (ΔLV end-systolic volume −40±29%; ΔLVEF +15±13%) (p<0.001 for all). Interestingly, following reverse remodeling, the LV function of stage LBBB-2, -3 and -4 patients improved to a similar LVEF of 38% (p=1.000) in this cohort. Patients in stage LBBB-0 had a significantly less favorable five-year outcome compared to those in stage LBBB≥1 (log-rank p=0.003). There was no difference in long-term outcome between stage LBBB-1 to −4 patients (log-rank p=0.510). Conclusion Strain-based LBBB staging predicts the extent of LV reverse remodeling in CRT patients. CRT did not translate into improved absolute survival in the more advanced stages, but the observed gradual volumetric response suggests that CRT corrects the LBBB-induced mortality. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

Time delay to peak left ventricular pressure rise identifies the substrate for dyssynchronous heart failure and detects disease modification with resynchronization- an observational clinical study

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East Health Authorities Introduction Identification of disease modification prior to implantation of Cardiac Resynchronization Therapy may help select the right patients, increase responder-rates and promote the utilization of CRT. We tested the hypothesis that shortening of time-to-peak left ventricular pressure rise (Td) with CRT is useful to predict long-term volumetric response (End-systolic volume (ESV) decrease >15%) to CRT. Methods Forty-five heart failure patients admitted for CRT implantation with a class I/IIa indication according to current ESC/AHA guidelines were included in the study. Td was measured from onset QRS at baseline and from onset of pacing with CRT. Results Baseline characteristics were mean age 63 ± 10 years , 71% males, NYHA class 2.5, 87% LBBB, QRS duration 173 ± 15ms, EF biplane 31 ± 1%, ESV 144 ± 12mL and end-diastolic volume 2044 ± 14mL. At 6-months follow-up six patients increased ESV by 5 ± 8%, while 37 responders (85%) had a mean ESV decrease of 40 ± 2%. Responders presented with a higher Td at baseline compared to non-responders (163 ± 4ms vs 119 ± 9ms, p < 0.01). Td decreased to 156 ± 4ms (p = 0.02) with CRT in responders, while in non-responders Td increased to 147 ± 10ms (p < 0.01) with CRT. A decrease in Td of less than +3.5ms from baseline accurately identified responders to therapy (AUC 0.98, p < 0.01, sensitivity 97%, specificity 100%). AUC was 0.92 for baseline Td and a cut-off at 120ms yielded a sensitivity of 100% and specificity of 80% to identify volumetric responders. A linear relationship between the change in Td from baseline and ESV decrease on long term was found (β=-61, R = 0.58, P < 0.01). Conclusions Td at baseline and the shortening of Td with CRT accurately identifies responders to CRT, with incremental value on top of current guidelines, in a population with already high response rates. Td carries the potential to become the marker for prediction of long-term volumetric response in CRT candidates. Abstract Figure.

Volumetric Response of Brain Oligometastatic Disease to Focal Hypofractionated Radiation Therapy

Background: This study aimed to assess the volumetric response, morbidity and failure rates of hypofractionated radiation therapy (HFRT) for definitive focal management of brain oligometastatic disease. Methods: Patients managed with HFRT for unresected oligometastatic brain disease were entered into an ethics-approved database. HFRT was delivered using IMRT or VMAT with 30Gy or 25Gy in 5 fractions. Individual lesions had volumetric assessment performed at three timepoints. Primary endpoint was change of volume from baseline (GTV0) to one-month post-HFRT (GTV1); and to seven-months post-HFRT (GTV7). Secondary endpoints were local failure, survival, and rate of radiation necrosis. Results:One hundred and twenty-four patients with 233 lesions were managed with HFRT. Median follow-up was 23.5 months with thirty-two (25.8%) patients alive at censure. Median overall survival was 7.3 months, with 36.3% survival at 12 months, with superior survival predicted by GTV0 (p=0.003) and percentage volumetric response (p<0.001). Systemic therapy was delivered in 81.5% of cases. At one-month post-HFRT 206 metastases (88.4%) were available for assessment; at seven-months post-HFRT this had reduced to 118 metastases (50.6%). Median metastasis volume at GTV0 was 1.6cm3 (range: 0.1-19.1). At GTV1 and GTV7 this reduced to 0.7cm3 (p<0.001) and 0.3cm3 (p<0.001) respectively, correlating to percentage reductions of 54.9% and 83.3%. No significant predictors of volumetric response following HFRT were identified. Local failure was confirmed in 4.3% of lesions and radiation necrosis in 3.9%. Conclusion: HFRT is an effective method for oligometastatic disease in the brain to maximise initial volumetric response whilst minimising pseudoprogression and radiation necrosis.

Triaxial Compression on Semi-solid Alloys

Multi-axial compression of the mushy zone occurs in various pressurized casting processes. Here, we present a drained triaxial compression apparatus for semi-solid alloys that allow liquid to be drawn into or expelled from the sample in response to isotropic or triaxial compression. The rig is used to measure the pressure-dependent flow stress and volumetric response during isothermal triaxial compression of globular semi-solid Al-15 wt pct Cu at 70 to 85 vol pct solid. Analysis of the stress paths and the stress–volume data show that the combination of the solid fraction and mean effective pressure determines whether the material undergoes shear-induced dilation or contraction. The results are compared with the critical state soil mechanics (CSSM) framework and the similarities and differences in behavior between equiaxed semi-solid alloys and soils are discussed.

NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

NIMG-44. INTEGRATING AUTOMATED LESION SEGMENTATIONS FROM SINGLE-IMAGES INTO ROUTINE CLINICAL WORKFLOW FOR VOLUMETRIC RESPONSE ASSESSMENT

INTRODUCTION Volume calculations have not been adopted into glioma response assessment due to lengthy times for manual definition and unreliable measures provided by automated algorithms. Relatively new artificial intelligence approaches such as convolutional neural networks have significantly improved lesion segmentation with performance accuracies &gt;90%. However, their adoption into routine practice remains limited due to poor generalizability and failure rates approaching 25% when incorporated into clinical workflow. The latter can be attributed to 1) the requirement of four different types of anatomic images (T2, T2-FLAIR, T1 pre- and post-contrast); 2) cumbersome preprocessing including alignment, reformatting, and skull removal; and 3) the lack of a well-integrated clinical deployment system. The goal of this study was to demonstrate how simple modifications to a robust network coupled with an integrated workflow can provide reliable measures of tumor volume for real-time use in the reading room. METHODS Leveraging NVIDIA’s Clara-Train software and a molecularly diverse dataset of 400 labeled images for training, we modified a top-performing ensembled 2D-U-Net to require a single image-volume input (T2-FLAIR or post-contrast T1 for the T2-hyperintense or contrast-enhancing lesions) and deployed the results in the clinic to provide quantitative volumetrics. Inference was performed on a mix of image orientations without any reformatting or skull-stripping. RESULTS Training on only 115 of our 400 datasets, we achieved Dice Coefficients of 90% and 81% overlap of our auto-segmented T2 and contrast-enhancing lesions with manual labels in our 25-patient validation cohort (11 enhancing), compared to 91% and 83% overlap with the original model that required four anatomic images to segment each lesion. Radiologists can view segmentations directly from PACS as contours or overlays and provide numerical feedback for model refinement. The workflow has been applied on 50 cases to date without any failures and can be easily shared for deployment on any clinical PACS.

Finite elasticity of elastomeric materials

This chapter presents several technologically important constitutive relations for elastomeric materials. In particular, the Neo-Hookean, Mooney-Rivlin, Ogden, Arruda-Boyce, and Gent free energy functions are discussed in the context of incompressible response. Extensions to the slightly compressible case are also detailed, this includes a presentation of a number of possible volumetric response relations and their properties.

P544Evaluation of three-dimensional trajectory of pacing cathode pole in coronary sinus to predict long-term response to cardiac resynchronization therapy

Background An automated method for 3D reconstruction of coronary sinus (CS) lead’s pacing cathode trajectory (3DTJ) was proposed to acutely predict long term left ventricular (LV) mechanic response to cardiac resynchronization therapy (CRT). Preliminary data showed that 3DTJ at biventricular pacing (BIV) start changed in CRT responders (R) to be, becoming less eccentric and more multi-directional, as described by the ratio between its two major axes (S1/S2). Purpose The TRAJECTORIES study (Trajectory Changes Of Coronary Sinus Lead Tip And Cardiac Resynchronization Therapy Outcome, NCT02340546) is an observational study by seven Italian centers about the prediction of CRT-induced LV reverse remodeling by means of the acute 3DTJ changes at CRT implant. Methods In CRT implants with standard indications, stable CHF and regular ventricular rhythm, a fluoroscopic sequence in two standard X-rays views of a few seconds was acquired immediately before (T-1) and after the start of BIV (T0). 3DTJ of CS lead cathode pole throughout the cardiac cycle at T-1 and T0 were reconstructed and analyzed. Changes of the ratio between its two major axes (S1/S2) between T-1 and T0 (ΔS1/S2), were compared with the volumetric response at six-month f.u: the percent negative variation of S1/S2 (ΔS1/S2 &lt; 0), marking a more multi-directional shape of 3DTJ, was assumed to predict the response to CRT. Volumetric response was adjudicated by a core-lab using a cut-off reduction ≥ 15% in echocardiographic LV end-systolic volume at f.u.. Results Out of 119 patients enrolled in 42 months, 74 pts ended f.u. (55 m; age 69 ± 10) and 30 dropped–out. Patients baseline features were: ischemic heart disease (IHD) 34 /74 pts; sinus rhythm 64/74 pts; upgrade from PM/ICD 13/74 pts; QRS morphology with LBBB 57/74, intraventricular aspecific delay 6 and RV pace 11 pts; LV ejection fraction (EF) 30 ± 9%; QRS duration 162 ± 25 ms. At f.u., volumetric R were 45/74 (60%). Concordance between ΔS1/S2 (as either ΔS1/S2 &lt; 0 or ΔS1/S2 &gt; 0) and volumetric response was 77% overall (57/74), 82% in R (37/45), 69% in non-R (20/29). Non-concordant patients were mostly non-R: 52% vs 35% of non-R in concordant group, but no other differences were found. The proposed 3DTJ metric showed sensitivity = 72%, specificity =80%; positive predictive value = 69%, negative predictive value = 82%. Conclusions Metrics of 3DTJ can be useful to acutely predict CS pacing site-specific response to CRT in long-term, above all in R. 3DTJ assessment might highlight aspects of CRT effects on LV mechanics.