Feature Tracking Cardiac Magnetic Resonance via Deep Learning and Spline Optimization

Feature tracking Cardiac Magnetic Resonance (CMR) has recently emerged as an area of interest for quantification of regional cardiac function from balanced, steady state free precession (SSFP) cine sequences. However, currently available techniques lack full automation, limiting reproducibility. We propose a fully automated technique whereby a CMR image sequence is first segmented with a deep, fully convolutional neural network (CNN) architecture, and quadratic basis splines are fitted simultaneously across all cardiac frames using least squares optimization. Experiments are performed using data from 42 patients with hypertrophic cardiomyopathy (HCM) and 21 healthy control subjects. In terms of segmentation, we compared state-of-the-art CNN frameworks, U-Net and dilated convolution architectures, with and without temporal context, using cross validation with three folds. Performance relative to expert manual segmentation was similar across all networks: pixel accuracy was ~97%, intersection-over-union (IoU) across all classes was ~87%, and IoU across foreground classes only was ~85%. Endocardial left ventricular circumferential strain calculated from the proposed pipeline was significantly different in control and disease subjects (-25.3% vs -29.1%, p = 0.006), in agreement with the current clinical literature.Comment: Accepted to Functional Imaging and Modeling of the Heart (FIMH) 201

Demonstration of Patient-Specific Simulations to Assess Left Atrial Appendage Thrombogenesis Risk

Atrial fibrillation (AF) alters left atrial (LA) hemodynamics, which can lead to thrombosis in the left atrial appendage (LAA), systemic embolism and stroke. A personalized risk-stratification of AF patients for stroke would permit improved balancing of preventive anticoagulation therapies against bleeding risk. We investigated how LA anatomy and function impact LA and LAA hemodynamics, and explored whether patient-specific analysis by computational fluid dynamics (CFD) can predict the risk of LAA thrombosis. We analyzed 4D-CT acquisitions of LA wall motion with an in-house immersed-boundary CFD solver. We considered six patients with diverse atrial function, three with either a LAA thrombus (removed digitally before running the simulations) or a history of transient ischemic attacks (LAAT/TIA-pos), and three without a LAA thrombus or TIA (LAAT/TIA-neg). We found that blood inside the left atrial appendage of LAAT/TIA-pos patients had marked alterations in residence time and kinetic energy when compared with LAAT/TIA-neg patients. In addition, we showed how the LA conduit, reservoir and booster functions distinctly affect LA and LAA hemodynamics. Finally, fixed-wall and moving-wall simulations produced different LA hemodynamics and residence time predictions for each patient. Consequently, fixed-wall simulations risk-stratified our small cohort for LAA thrombosis worse than moving-wall simulations, particularly patients with intermediate LAA residence time. Overall, these results suggest that both wall kinetics and LAA morphology contribute to LAA blood stasis and thrombosis.This work was partially supported by the Comunidad de Madrid (Sinergias Y2018/BIO-4858 PREFI-CM), Cátedra Excelencia UC3M-Santander, Ministry of Education of Spain (Salvador de Madariaga program), the US NHLBI (NCAI-UCCAI-2017-06-6), the United States American Heart Association (AHA 20POST35200401), and the 2019 UCSD GEM Program. Computational time provided by XSEDE (Comet) and RES (Altamira) is gratefully acknowledged

Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy

Background: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). Method Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15). Results: LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both). Conclusion: LA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis. Electronic supplementary material The online version of this article (10.1186/s12968-017-0420-0) contains supplementary material, which is available to authorized users

DMSO and Betaine Greatly Improve Amplification of GC-Rich Constructs in De Novo Synthesis

In Synthetic Biology, de novo synthesis of GC-rich constructs poses a major challenge because of secondary structure formation and mispriming. While there are many web-based tools for codon optimizing difficult regions, no method currently exists that allows for potentially phenotypically important sequence conservation. Therefore, to overcome these limitations in researching GC-rich genes and their non-coding elements, we explored the use of DMSO and betaine in two conventional methods of assembly and amplification. For this study, we compared the polymerase (PCA) and ligase-based (LCR) methods for construction of two GC-rich gene fragments implicated in tumorigenesis, IGF2R and BRAF. Though we found no benefit in employing either DMSO or betaine during the assembly steps, both additives greatly improved target product specificity and yield during PCR amplification. Of the methods tested, LCR assembly proved far superior to PCA, generating a much more stable template to amplify from. We further report that DMSO and betaine are highly compatible with all other reaction components of gene synthesis and do not require any additional protocol modifications. Furthermore, we believe either additive will allow for the production of a wide variety of GC-rich gene constructs without the need for expensive and time-consuming sample extraction and purification prior to downstream application

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Quantification of regional cardiac function: clinically-motivated algorithm development and application to cardiac magnetic resonance and computed tomography

Techniques described to date for the reproducible and noninvasive quantification of regional cardiac function have been largely relegated to research settings due to time-consuming and cumbersome image acquisition and analysis. In this thesis, feature tracking algorithms are developed for 2-D+Time cardiac magnetic resonance (CMR) and 3-D+Time cardiac computed tomography (CCT) image sequences that are easily acquired clinically, while emphasising reproducibility and automation in their design. First, a commercially-implemented CMR feature tracking algorithm for the analysis of steady state free precession (SSFP) cine series is evaluated in patients with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), which primarily affect the left ventricle (LV) and right ventricle (RV), respectively, and functional impairment compared with control populations is found in both cases. The limitations of this implementation are then used to guide development of an automated algorithm for the same purpose, making use of fully convolutional neural networks (CNN) for segmentation and spline registration across all frames simultaneously for tracking. This study is performed in the subjects with HCM, and functional impairment is again identified in disease subjects. Finally, as myocardial contraction is inherently a 3-D phenomenon, a technique is developed for quantification of regional function from 3-D+Time functional CCT studies using simultaneous registration of automatically generated Loop subdivision surface models for tracking. This study is performed in canine mongrels, and compared with the current state of the art technique for CCT functional analysis. This work demonstrates the feasibility of automated, reproducible cardiac functional analysis from CMR and CCT image sequences. While work remains to be done in extending the principles demonstrated and modular components described to fully automated whole-heart analysis, it is hoped that this thesis will accelerate the clinical adoption of regional functional analysis

Quantification of regional cardiac function: clinically-motivated algorithm development and application to cardiac magnetic resonance and computed tomography

Techniques described to date for the reproducible and noninvasive quantification of regional cardiac function have been largely relegated to research settings due to time-consuming and cumbersome image acquisition and analysis. In this thesis, feature tracking algorithms are developed for 2-D+Time cardiac magnetic resonance (CMR) and 3-D+Time cardiac computed tomography (CCT) image sequences that are easily acquired clinically, while emphasising reproducibility and automation in their design. First, a commercially-implemented CMR feature tracking algorithm for the analysis of steady state free precession (SSFP) cine series is evaluated in patients with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), which primarily affect the left ventricle (LV) and right ventricle (RV), respectively, and functional impairment compared with control populations is found in both cases. The limitations of this implementation are then used to guide development of an automated algorithm for the same purpose, making use of fully convolutional neural networks (CNN) for segmentation and spline registration across all frames simultaneously for tracking. This study is performed in the subjects with HCM, and functional impairment is again identified in disease subjects. Finally, as myocardial contraction is inherently a 3-D phenomenon, a technique is developed for quantification of regional function from 3-D+Time functional CCT studies using simultaneous registration of automatically generated Loop subdivision surface models for tracking. This study is performed in canine mongrels, and compared with the current state of the art technique for CCT functional analysis. This work demonstrates the feasibility of automated, reproducible cardiac functional analysis from CMR and CCT image sequences. While work remains to be done in extending the principles demonstrated and modular components described to fully automated whole-heart analysis, it is hoped that this thesis will accelerate the clinical adoption of regional functional analysis.</p

Vascular Landmark-Based Method for Highly Reproducible Measurement of Left Atrial Appendage Volume in Computed Tomography.

BackgroundModern computed tomographic scanning can produce 4-dimensional images of the left atrial appendage (LAA). LAA function and morphology can then be measured, to plan interventions such as occlusion and to evaluate LAA flow for thrombogenic risk analysis. A current problem here is defining a reproducible boundary between the LAA and the left atrium.MethodsThis study used retrospectively gated 4-dimensional computed tomographic data from 25 implantation and coronary artery imaging patients. In each patient, the LAA ostium was defined at multiple time points during the RR interval. To examine the reproducibility of the definition of the LAA ostium, 3 observers analyzed all time frames in each patient 3 times. Five nonconsecutive time frames from each patient were then compared using intraclass correlation coefficients to quantify the precision of the method across patients. The correlation of LAA volumes for each time frame of each patient was determined across the different observers (interobserver) and within each observer's own data sets (intraobserver).ResultsThe method was successful in 92% of patients. Two-way random-effect, absolute-agreement, single-measurement intraclass correlation coefficients for interobserver measurements were 0.984, 0.990, and 0.988, with intraobserver intraclass correlation coefficients of 0.989, 0.989, and 0.995. The intraclass correlation coefficient of all observations was 0.988.ConclusionsClassification of the LAA ostium using a stepwise procedure identifying the coumadin ridge and 2 vascular landmarks in ECG-gated computed tomography provides a viable method of establishing a highly reproducible boundary between the atrium and LAA needed to obtain LAA metrics useful for procedure planning and measuring LAA function