Risk Stratification, Screening and Treatment of BRAF/MEK Inhibitors-Associated Cardiotoxicity.

PURPOSE OF REVIEW: In this review article we describe the cardiovascular adverse events associated with BRAF and MEK inhibitors as well as their pathophysiologic mechanisms and provide up to date guidance for risk stratified surveillance of patients on treatment and the optimal management of emergent cardiotoxicities. RECENT FINDINGS: Combination BRAF/MEK inhibition has become an established standard treatment option for patients with a wide variety of BRAF mutant haematological and solid organ cancers, its use is most commonly associated with stage three and metastatic melanoma. The introduction of these targeted drugs has significantly improved the prognosis of previously treatment resistant cancers. It is increasingly recognised that these drugs have a number of cardiovascular toxicities including left ventricular systolic dysfunction, hypertension and QTc interval prolongation. Whilst cardiotoxicity is largely reversible and manageable with medical therapy, it does limit the effective use of these highly active agents.

Automated segmentation of long and short axis DENSE cardiovascular magnetic resonance for myocardial strain analysis using spatio-temporal convolutional neural networks.

BACKGROUND: Cine Displacement Encoding with Stimulated Echoes (DENSE) facilitates the quantification of myocardial deformation, by encoding tissue displacements in the cardiovascular magnetic resonance (CMR) image phase, from which myocardial strain can be estimated with high accuracy and reproducibility. Current methods for analyzing DENSE images still heavily rely on user input, making this process time-consuming and subject to inter-observer variability. The present study sought to develop a spatio-temporal deep learning model for segmentation of the left-ventricular (LV) myocardium, as spatial networks often fail due to contrast-related properties of DENSE images. METHODS: 2D + time nnU-Net-based models have been trained to segment the LV myocardium from DENSE magnitude data in short- and long-axis images. A dataset of 360 short-axis and 124 long-axis slices was used to train the networks, from a combination of healthy subjects and patients with various conditions (hypertrophic and dilated cardiomyopathy, myocardial infarction, myocarditis). Segmentation performance was evaluated using ground-truth manual labels, and a strain analysis using conventional methods was performed to assess strain agreement with manual segmentation. Additional validation was performed using an externally acquired dataset to compare the inter- and intra-scanner reproducibility with respect to conventional methods. RESULTS: Spatio-temporal models gave consistent segmentation performance throughout the cine sequence, while 2D architectures often failed to segment end-diastolic frames due to the limited blood-to-myocardium contrast. Our models achieved a DICE score of 0.83 ± 0.05 and a Hausdorff distance of 4.0 ± 1.1 mm for short-axis segmentation, and 0.82 ± 0.03 and 7.9 ± 3.9 mm respectively for long-axis segmentations. Strain measurements obtained from automatically estimated myocardial contours showed good to excellent agreement with manual pipelines, and remained within the limits of inter-user variability estimated in previous studies. CONCLUSION: Spatio-temporal deep learning shows increased robustness for the segmentation of cine DENSE images. It provides excellent agreement with manual segmentation for strain extraction. Deep learning will facilitate the analysis of DENSE data, bringing it one step closer to clinical routine.

Quantification of balanced SSFP myocardial perfusion imaging at 1.5 T: Impact of the reference image.

PURPOSE: To investigate the use of a high flip-angle (HFA) balanced SSFP (bSSFP) reference image (in comparison to conventional proton density [PD]-weighted reference images) for conversion of bSSFP myocardial perfusion images into dynamic T1 maps for improved myocardial blood flow (MBF) quantification at 1.5 T. METHODS: The HFA-bSSFP (flip angle [FA] = 50°), PD gradient-echo (PD-GRE; FA = 5°), and PD-bSSFP (FA = 8°) reference images were acquired before a dual-sequence bSSFP perfusion acquisition. Simulations were used to study accuracy and precision of T1 and MBF quantification using the three techniques. The accuracy and precision of T1 , and the precision and intersegment variability of MBF were compared among the three techniques in 8 patients under rest conditions. RESULTS: In simulations, HFA-bSSFP demonstrated improved T1 /MBF precision (higher T1 /MBF SD of 30%-80%/50%-100% and 30%-90%/60%-115% for PD-GRE and PD-bSSFP, respectively). Proton density-GRE and PD-bSSFP were more sensitive to effective FA than HFA-bSSFP (maximum T1 /MBF errors of 13%/43%, 20%/43%, and 1%/3%, respectively). Sensitivity of all techniques (defined as T1 /MBF errors) to native T1 , native T2 , and effective saturation efficiency were negligible (<1%/<1%), moderate (<14%/<19%), and high (<63%/<94%), respectively. In vivo, no difference in T1 accuracy was observed among HFA-bSSFP, PD-GRE, and PD-bSSFP (-9 ± 44 ms vs -28 ± 55 ms vs -22 ± 71 ms, respectively; p > .08). The HFA-bSSFP led to improved T1 /MBF precision (T1 /MBF SD: 41 ± 19 ms/0.24 ± 0.08 mL/g/min vs PD-GRE: 48 ± 20 ms/0.29 ± 0.09 mL/g/min and PD-bSSFP: 59 ± 23 ms/0.33 ± 0.11 mL/g/min; p ≤ .02) and lower MBF intersegment variability (0.14 ± 0.09 mL/g/min vs PD-GRE: 0.21 ± 0.09 mL/g/min and PD-bSSFP: 0.20 ± 0.10 mL/g/min; p ≤ .046). CONCLUSION: We have demonstrated the feasibility of using a HFA-bSSFP reference image for MBF quantification of bSSFP perfusion imaging at 1.5 T. Results from simulations demonstrate that the HFA-bSSFP reference image results in improved precision and reduced sensitivity to effective FA compared with conventional techniques using a PD reference image. Preliminary in vivo data acquired at rest also demonstrate improved precision and intersegment variability using the HFA-bSSFP technique compared with PD techniques; however, a clinical study in patients with coronary artery disease under stress conditions is required to determine the clinical significance of this finding.

Simultaneous multislice steady-state free precession myocardial perfusion with full left ventricular coverage and high resolution at 1.5 T.

PURPOSE: To implement and evaluate a simultaneous multi-slice balanced SSFP (SMS-bSSFP) perfusion sequence and compressed sensing reconstruction for cardiac MR perfusion imaging with full left ventricular (LV) coverage (nine slices/heartbeat) and high spatial resolution (1.4 × 1.4 mm2 ) at 1.5T. METHODS: A preliminary study was performed to evaluate the performance of blipped controlled aliasing in parallel imaging (CAIPI) and RF-CAIPI with gradient-controlled local Larmor adjustment (GC-LOLA) in the presence of fat. A nine-slice SMS-bSSFP sequence using RF-CAIPI with GC-LOLA with high spatial resolution (1.4 × 1.4 mm2 ) and a conventional three-slice sequence with conventional spatial resolution (1.9 × 1.9 mm2 ) were then acquired in 10 patients under rest conditions. Qualitative assessment was performed to assess image quality and perceived signal-to-noise ratio (SNR) on a 4-point scale (0: poor image quality/low SNR; 3: excellent image quality/high SNR), and the number of myocardial segments with diagnostic image quality was recorded. Quantitative measurements of myocardial sharpness and upslope index were performed. RESULTS: Fat signal leakage was significantly higher for blipped CAIPI than for RF-CAIPI with GC-LOLA (7.9% vs. 1.2%, p = 0.010). All 10 SMS-bSSFP perfusion datasets resulted in 16/16 diagnostic myocardial segments. There were no significant differences between the SMS and conventional acquisitions in terms of image quality (2.6 ± 0.6 vs. 2.7 ± 0.2, p = 0.8) or perceived SNR (2.8 ± 0.3 vs. 2.7 ± 0.3, p = 0.3). Inter-reader variability was good for both image quality (ICC = 0.84) and perceived SNR (ICC = 0.70). Myocardial sharpness was improved using the SMS sequence compared to the conventional sequence (0.37 ± 0.08 vs 0.32 ± 0.05, p < 0.001). There was no significant difference between measurements of upslope index for the SMS and conventional sequences (0.11 ± 0.04 vs. 0.11 ± 0.03, p = 0.84). CONCLUSION: SMS-bSSFP with multiband factor 3 and compressed sensing reconstruction enables cardiac MR perfusion imaging with three-fold increased spatial coverage and improved myocardial sharpness compared to a conventional sequence, without compromising perceived SNR, image quality, upslope index or number of diagnostic segments.

Impact of Temporal Resolution and Methods for Correction on Cardiac Magnetic Resonance Perfusion Quantification.

BACKGROUND: Acquisition of magnetic resonance first-pass perfusion images is synchronized to the patient's heart rate (HR) and governs the temporal resolution. This is inherently linked to the process of myocardial blood flow (MBF) quantification and impacts MBF accuracy but to an unclear extent. PURPOSE: To assess the impact of temporal resolution on quantitative perfusion and compare approaches for accounting for its variability. STUDY TYPE: Prospective phantom and retrospective clinical study. POPULATION AND PHANTOM: Simulations, a cardiac perfusion phantom, and 30 patients with (16, 53%) or without (14, 47%) coronary artery disease. FIELD STRENGTH/SEQUENCE: 3.0 T/2D saturation recovery spoiled gradient echo sequence. ASSESSMENT: Dynamic perfusion data were simulated for a range of reference MBF (1 mL/g/min-5 mL/g/min) and HR (30 bpm-150 bpm). Perfusion imaging was performed in patients and a phantom for different temporal resolutions. MBF and myocardial perfusion reserve (MPR) were quantified without correction for temporal resolution or following correction by either MBF scaling based on the sampling interval or data interpolation prior to quantification. Simulated data were quantified using Fermi deconvolution, truncated singular value decomposition, and one-compartment modeling, whereas phantom and clinical data were quantified using Fermi deconvolution alone. STATISTICAL TESTS: Shapiro-Wilk tests for normality, percentage error (PE) for measuring MBF accuracy in simulations, and one-way repeated measures analysis of variance with Bonferroni correction to compare clinical MBF and MPR. Statistical significance set at P < 0.05. RESULTS: For Fermi deconvolution and an example simulated 1 mL/g/min, the MBF PE without correction for temporal resolution was between 55.4% and -62.7% across 30-150 bpm. PE was between -22.2% and -6.8% following MBF scaling and between -14.2% and -14.2% following data interpolation across the same HR. An interpolated HR of 240 bpm reduced PE to ≤10%. Clinical rest and stress MBF and MPR were significantly different between analyses. DATA CONCLUSION: Accurate perfusion quantification needs to account for the variability of temporal resolution, with data interpolation prior to quantification reducing MBF variability across different resolutions. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1.

High-resolution non-contrast free-breathing coronary cardiovascular magnetic resonance angiography for detection of coronary artery disease: validation against invasive coronary angiography.

BACKGROUND: Coronary artery disease (CAD) is the single most common cause of death worldwide. Recent technological developments with coronary cardiovascular magnetic resonance angiography (CCMRA) allow high-resolution free-breathing imaging of the coronary arteries at submillimeter resolution without contrast in a predictable scan time of ~ 10 min. The objective of this study was to determine the diagnostic accuracy of high-resolution CCMRA for CAD detection against the gold standard of invasive coronary angiography (ICA). METHODS: Forty-five patients (15 female, 62 ± 10 years) with suspected CAD underwent sub-millimeter-resolution (0.6 mm3) non-contrast CCMRA at 1.5T in this prospective clinical study from 2019-2020. Prior to CCMR, patients were given an intravenous beta blockers to optimize heart rate control and sublingual glyceryl trinitrate to promote coronary vasodilation. Obstructive CAD was defined by lesions with ≥ 50% stenosis by quantitative coronary angiography on ICA. RESULTS: The mean duration of image acquisition was 10.4 ± 2.1 min. On a per patient analysis, the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 95% (75-100), 54% (36-71), 60% (42-75) and 93% (70-100), respectively. On a per vessel analysis the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 80% (63-91), 83% (77-88), 49% (36-63) and 95% (90-98), respectively. CONCLUSION: As an important step towards clinical translation, we demonstrated a good diagnostic accuracy for CAD detection using high-resolution CCMRA, with high sensitivity and negative predictive value. The positive predictive value is moderate, and combination with CMR stress perfusion may improve the diagnostic accuracy. Future multicenter evaluation is now required.

A fast navigator (fastNAV) for prospective respiratory motion correction in first-pass myocardial perfusion imaging.

PURPOSE: To develop and evaluate a fast respiratory navigator (fastNAV) for cardiac MR perfusion imaging with subject-specific prospective slice tracking. METHODS: A fastNAV was developed for dynamic contrast-enhanced cardiac MR perfusion imaging by combining spatially nonselective saturation with slice-selective tip-up and slice-selective excitation pulses. The excitation slice was angulated from the tip-up slice in the transverse plane to overlap only in the right hemidiaphragm for suppression of signal outside the right hemidiaphragm. A calibration scan was developed to enable the estimation of subject-specific tracking factors. Perfusion imaging using subject-specific fastNAV-based slice tracking was then compared to a conventional sequence (ie, without slice tracking) in 10 patients under free-breathing conditions. Respiratory motion in perfusion images was quantitatively assessed by measuring the average overlap of the left ventricle across images (avDice, 0:no overlap/1:perfect overlap) and the average displacement of the center of mass of the left ventricle (avCoM). Image quality was subjectively assessed using a 4-point scoring system (1: poor, 4: excellent). RESULTS: The fastNAV calibration was successfully performed in all subjects (average tracking factor of 0.46 ± 0.13, R = 0.94 ± 0.03). Prospective motion correction using fastNAV led to higher avDice (0.94 ± 0.02 vs. 0.90 ± 0.03, P < .001) and reduced avCoM (4.03 ± 0.84 vs. 5.22 ± 1.22, P < .001). There were no statistically significant differences between the 2 sequences in terms of image quality (both sequences: median = 3 and interquartile range = 3-4, P = 1). CONCLUSION: fastNAV enables fast and robust right hemidiaphragm motion tracking in a perfusion sequence. In combination with subject-specific slice tracking, fastNAV reduces the effect of respiratory motion during free-breathing cardiac MR perfusion imaging.

All-systolic first-pass myocardial rest perfusion at a long saturation time using simultaneous multi-slice imaging and compressed sensing acceleration.

PURPOSE: To enable all-systolic first-pass rest myocardial perfusion with long saturation times. To investigate the change in perfusion contrast and dark rim artefacts through simulations and surrogate measurements. METHODS: Simulations were employed to investigate optimal saturation time for myocardium-perfusion defect contrast and blood-to-myocardium signal ratios. Two saturation recovery blocks with long/short saturation times (LTS/STS) were employed to image 3 slices at end-systole and diastole. Simultaneous multi-slice balanced steady state free precession imaging and compressed sensing acceleration were combined. The sequence was compared to a 3 slice-by-slice clinical protocol in 10 patients. Quantitative assessment of myocardium-peak pre contrast and blood-to-myocardium signal ratios, as well as qualitative assessment of perceived SNR, image quality, blurring, and dark rim artefacts, were performed. RESULTS: Simulations showed that with a bolus of 0.075 mmol/kg, a LTS of 240-470 ms led to a relative increase in myocardium-perfusion defect contrast of 34% ± 9%-28% ± 27% than a STS = 120 ms, while reducing blood-to-myocardium signal ratio by 18% ± 10%-32% ± 14% at peak myocardium. With a bolus of 0.05 mmol/kg, LTS was 320-570 ms with an increase in myocardium-perfusion defect contrast of 63% ± 13%-62% ± 29%. Across patients, LTS led to an average increase in myocardium-peak pre contrast of 59% (P < .001) at peak myocardium and a lower blood-to-myocardium signal ratio of 47% (P < .001) and 15% (P < .001) at peak blood/myocardium. LTS had improved motion robustness (P = .002), image quality (P < .001), and decreased dark rim artefacts (P = .008) than the clinical protocol. CONCLUSION: All-systolic rest perfusion can be achieved by combining simultaneous multi-slice and compressed sensing acceleration, enabling 3-slice cardiac coverage with reduced motion and dark rim artefacts. Numerical simulations indicate that myocardium-perfusion defect contrast increases at LTS.

Clinical comparison of sub-mm high-resolution non-contrast coronary CMR angiography against coronary CT angiography in patients with low-intermediate risk of coronary artery disease: a single center trial.

BACKGROUND: The widespread clinical application of coronary cardiovascular magnetic resonance (CMR) angiography (CMRA) for the assessment of coronary artery disease (CAD) remains limited due to low scan efficiency leading to prolonged and unpredictable acquisition times; low spatial-resolution; and residual respiratory motion artefacts resulting in limited image quality. To overcome these limitations, we have integrated highly undersampled acquisitions with image-based navigators and non-rigid motion correction to enable high resolution (sub-1 mm3) free-breathing, contrast-free 3D whole-heart coronary CMRA with 100% respiratory scan efficiency in a clinically feasible and predictable acquisition time. OBJECTIVES: To evaluate the diagnostic performance of this coronary CMRA framework against coronary computed tomography angiography (CTA) in patients with suspected CAD. METHODS: Consecutive patients (n = 50) with suspected CAD were examined on a 1.5T CMR scanner. We compared the diagnostic accuracy of coronary CMRA against coronary CTA for detecting a ≥ 50% reduction in luminal diameter. RESULTS: The 50 recruited patients (55 ± 9 years, 33 male) completed coronary CMRA in 10.7 ± 1.4 min. Twelve (24%) had significant CAD on coronary CTA. Coronary CMRA obtained diagnostic image quality in 95% of all, 97% of proximal, 97% of middle and 90% of distal coronary segments. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were: per patient (100%, 74%, 55%, 100% and 80%), per vessel (81%, 88%, 46%, 97% and 88%) and per segment (76%, 95%, 44%, 99% and 94%) respectively. CONCLUSIONS: The high diagnostic image quality and diagnostic performance of coronary CMRA compared against coronary CTA demonstrates the potential of coronary CMRA as a robust and safe non-invasive alternative for excluding significant disease in patients at low-intermediate risk of CAD.

Pixel-wise assessment of cardiovascular magnetic resonance first-pass perfusion using a cardiac phantom mimicking transmural myocardial perfusion gradients.

PURPOSE: Cardiovascular magnetic resonance first-pass perfusion for the pixel-wise detection of coronary artery disease is rapidly becoming the clinical standard, yet no widely available method exists for its assessment and validation. This study introduces a novel phantom capable of generating spatially dependent flow values to enable assessment of new perfusion imaging methods at the pixel level. METHODS: A synthetic multicapillary myocardial phantom mimicking transmural myocardial perfusion gradients was designed and manufactured with high-precision 3D printing. The phantom was used in a stationary flow setup providing reference myocardial perfusion rates and was scanned on a 3T system. Repeated first-pass perfusion MRI for physiological perfusion rates between 1 and 4 mL/g/min was performed using a clinical dual-sequence technique. Fermi function-constrained deconvolution was used to estimate pixel-wise perfusion rate maps. Phase contrast (PC)-MRI was used to obtain velocity measurements that were converted to perfusion rates for validation of reference values and cross-method comparison. The accuracy of pixel-wise maps was assessed against simulated reference maps. RESULTS: PC-MRI indicated excellent reproducibility in perfusion rate (coefficient of variation [CoV] 2.4-3.5%) and correlation with reference values (R2 = 0.985) across the full physiological range. Similar results were found for first-pass perfusion MRI (CoV 3.7-6.2%, R2 = 0.987). Pixel-wise maps indicated a transmural perfusion difference of 28.8-33.7% for PC-MRI and 23.8-37.7% for first-pass perfusion, matching the reference values (30.2-31.4%). CONCLUSION: The unique transmural perfusion pattern in the phantom allows effective pixel-wise assessment of first-pass perfusion acquisition protocols and quantification algorithms before their introduction into routine clinical use.

Combined simultaneous multislice bSSFP and compressed sensing for first-pass myocardial perfusion at 1.5 T with high spatial resolution and coverage.

PURPOSE: To implement and evaluate a pseudorandom undersampling scheme for combined simultaneous multislice (SMS) balanced SSFP (bSSFP) and compressed-sensing (CS) reconstruction to enable myocardial perfusion imaging with high spatial resolution and coverage at 1.5 T. METHODS: A prospective pseudorandom undersampling scheme that is compatible with SMS-bSSFP phase-cycling requirements and CS was developed. The SMS-bSSFP CS with pseudorandom and linear undersampling schemes were compared in a phantom. A high-resolution (1.4 × 1.4 mm2 ) six-slice SMS-bSSFP CS perfusion sequence was compared with a conventional (1.9 × 1.9 mm2 ) three-slice sequence in 10 patients. Qualitative assessment of image quality, perceived SNR, and number of diagnostic segments and quantitative measurements of sharpness, upslope index, and contrast ratio were performed. RESULTS: In phantom experiments, pseudorandom undersampling resulted in residual artifact (RMS error) reduction by a factor of 7 compared with linear undersampling. In vivo, the proposed sequence demonstrated higher perceived SNR (2.9 ± 0.3 vs. 2.2 ± 0.6, P = .04), improved sharpness (0.35 ± 0.03 vs. 0.32 ± 0.05, P = .01), and a higher number of diagnostic segments (100% vs. 94%, P = .03) compared with the conventional sequence. There were no significant differences between the sequences in terms of image quality (2.5 ± 0.4 vs. 2.8 ± 0.2, P = .08), upslope index (0.11 ± 0.02 vs. 0.10 ± 0.01, P = .3), or contrast ratio (3.28 ± 0.35 vs. 3.36 ± 0.43, P = .7). CONCLUSION: A pseudorandom k-space undersampling compatible with SMS-bSSFP and CS reconstruction has been developed and enables cardiac MR perfusion imaging with increased spatial resolution and myocardial coverage, increased number of diagnostic segments and perceived SNR, and no difference in image quality, upslope index, and contrast ratio.

FASt single-breathhold 2D multislice myocardial T1 mapping (FAST1) at 1.5T for full left ventricular coverage in three breathholds.

BACKGROUND: Conventional myocardial T1 mapping techniques such as modified Look-Locker inversion recovery (MOLLI) generate one T1 map per breathhold. T1 mapping with full left ventricular coverage may be desirable when spatial T1 variations are expected. This would require multiple breathholds, increasing patient discomfort and prolonging scan time. PURPOSE: To develop and characterize a novel FASt single-breathhold 2D multislice myocardial T1 mapping (FAST1) technique for full left ventricular coverage. STUDY TYPE: Prospective. POPULATION/PHANTOM: Numerical simulation, agarose/NiCl2 phantom, 9 healthy volunteers, and 17 patients. FIELD STRENGTH/SEQUENCE: 1.5T/FAST1. ASSESSMENT: Two FAST1 approaches, FAST1-BS and FAST1-IR, were characterized and compared with standard 5-(3)-3 MOLLI in terms of accuracy, precision/spatial variability, and repeatability. STATISTICAL TESTS: Kruskal-Wallis, Wilcoxon signed rank tests, intraclass correlation coefficient analysis, analysis of variance, Student's t-tests, Pearson correlation analysis, and Bland-Altman analysis. RESULTS: In simulation/phantom, FAST1-BS, FAST1-IR, and MOLLI had an accuracy (expressed as T1 error) of 0.2%/4%, 6%/9%, and 4%/7%, respectively, while FAST1-BS and FAST1-IR had a precision penalty of 1.7/1.5 and 1.5/1.4 in comparison with MOLLI, respectively. In healthy volunteers, FAST1-BS/FAST1-IR/MOLLI led to different native myocardial T1 times (1016 ± 27 msec/952 ±22 msec/987 ± 23 msec, P < 0.0001) and spatial variability (66 ± 10 msec/57 ± 8 msec/46 ± 7 msec, P < 0.001). There were no statistically significant differences between all techniques for T1 repeatability (P = 0.18). In vivo native and postcontrast myocardial T1 times in both healthy volunteers and patients using FAST1-BS/FAST1-IR were highly correlated with MOLLI (Pearson correlation coefficient ≥0.93). DATA CONCLUSION: FAST1 enables myocardial T1 mapping with full left ventricular coverage in three separated breathholds. In comparison with MOLLI, FAST1 yield a 5-fold increase of spatial coverage, limited penalty of T1 precision/spatial variability, no significant difference of T1 repeatability, and highly correlated T1 times. FAST1-IR provides improved T1 precision/spatial variability but reduced accuracy when compared with FAST1-BS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:492-504.

Fast myocardial T1 mapping using shortened inversion recovery based schemes.

BACKGROUND: Myocardial T1 mapping shows promise for assessment of cardiomyopathies. Most myocardial T1 mapping techniques, such as modified Look-Locker inversion recovery (MOLLI), generate one T1 map per breath-held acquisition (9-17 heartbeats), which prolongs multislice protocols and may be unsuitable for patients with breath-holding difficulties. PURPOSE: To develop and characterize novel shortened inversion recovery based T1 mapping schemes of 2-5 heartbeats. STUDY TYPE: Prospective. POPULATION/PHANTOM: Numerical simulations, agarose/NiCl2 phantom, 16 healthy volunteers, and 24 patients. FIELD STRENGTH/SEQUENCE: 1.5T/MOLLI. ASSESSMENT: All shortened T1 mapping schemes were characterized and compared with a conventional MOLLI scheme (5-(3)-3) in terms of accuracy, precision, spatial variability, and repeatability. STATISTICAL TESTS: Kruskal-Wallis, Wilcoxon rank sum tests, analysis of variance, Student's t-tests, Bland-Altman analysis, and Pearson correlation analysis. RESULTS: All shortened schemes provided limited T1 time variations (≤2% for T1 times ≤1200 msec) and limited penalty of precision (by a factor of ~1.4-1.5) when compared with MOLLI in numerical simulations. In phantom, differences between all schemes in terms of accuracy, spatial variability, and repeatability did not reach statistical significance (P > 0.71). In healthy volunteers, there were no statistically significant differences between all schemes in terms of native T1 times and repeatability for myocardium (P = 0.21 and P = 0.87, respectively) and blood (P = 0.79 and P = 0.41, respectively). All shortened schemes led to a limited increase of spatial variability for native myocardial T1 mapping with respect to MOLLI (by a factor of 1.2) (P < 0.0001). In both healthy volunteers and patients, the two-heartbeat scheme and MOLLI led to highly linearly correlated T1 times (correlation coefficients ≥0.83). DATA CONCLUSION: The proposed two-heartbeat T1 mapping scheme yields a 5-fold acceleration compared with MOLLI, with highly linearly correlated T1 times, no significant difference of repeatability, and limited spatial variability penalty at 1.5T. This approach may enable myocardial T1 mapping in patients with severe breath-holding difficulties and reduce the examination time of multislice protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:641-654.

Clinical value of dark-blood late gadolinium enhancement cardiovascular magnetic resonance without additional magnetization preparation.

BACKGROUND: For two decades, bright-blood late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) has been considered the reference standard for the non-invasive assessment of myocardial viability. While bright-blood LGE can clearly distinguish areas of myocardial infarction from viable myocardium, it often suffers from poor scar-to-blood contrast, making subendocardial scar difficult to detect. Recently, we proposed a novel dark-blood LGE approach that increases scar-to-blood contrast and thereby improves subendocardial scar conspicuity. In the present study we sought to assess the clinical value of this novel approach in a large patient cohort with various non-congenital ischemic and non-ischemic cardiomyopathies on both 1.5 T and 3 T CMR scanners of different vendors. METHODS: Three hundred consecutive patients referred for clinical CMR were randomly assigned to a 1.5 T or 3 T scanner. An entire short-axis stack and multiple long-axis views were acquired using conventional phase sensitive inversion recovery (PSIR) LGE with TI set to null myocardium (bright-blood) and proposed PSIR LGE with TI set to null blood (dark-blood), in a randomized order. The bright-blood LGE and dark-blood LGE images were separated, anonymized, and interpreted in a random order at different time points by one of five independent observers. Each case was analyzed for the type of scar, per-segment transmurality, papillary muscle enhancement, overall image quality, observer confidence, and presence of right ventricular scar and intraventricular thrombus. RESULTS: Dark-blood LGE detected significantly more cases with ischemic scar compared to conventional bright-blood LGE (97 vs 89, p = 0.008), on both 1.5 T and 3 T, and led to a significantly increased total scar burden (3.3 ± 2.4 vs 3.0 ± 2.3 standard AHA segments, p = 0.015). Overall image quality significantly improved using dark-blood LGE compared to bright-blood LGE (81.3% vs 74.0% of all segments were of highest diagnostic quality, p = 0.006). Furthermore, dark-blood LGE led to significantly higher observer confidence (confident in 84.2% vs 78.4%, p = 0.033). CONCLUSIONS: The improved detection of ischemic scar makes the proposed dark-blood LGE method a valuable diagnostic tool in the non-invasive assessment of myocardial scar. The applicability in routine clinical practice is further strengthened, as the present approach, in contrast to other recently proposed dark- and black-blood LGE techniques, is readily available without the need for scanner adjustments, extensive optimizations, or additional training.

Simultaneous multi slice (SMS) balanced steady state free precession first-pass myocardial perfusion cardiovascular magnetic resonance with iterative reconstruction at 1.5 T.

BACKGROUND: Simultaneous-Multi-Slice (SMS) perfusion imaging has the potential to acquire multiple slices, increasing myocardial coverage without sacrificing in-plane spatial resolution. To maximise signal-to-noise ratio (SNR), SMS can be combined with a balanced steady state free precession (bSSFP) readout. Furthermore, application of gradient-controlled local Larmor adjustment (GC-LOLA) can ensure robustness against off-resonance artifacts and SNR loss can be mitigated by applying iterative reconstruction with spatial and temporal regularisation. The objective of this study was to compare cardiovascular magnetic resonance (CMR) myocardial perfusion imaging using SMS bSSFP imaging with GC-LOLA and iterative reconstruction to 3 slice bSSFP. METHODS: Two contrast-enhanced rest perfusion sequences were acquired in random order in 8 patients: 6-slice SMS bSSFP and 3 slice bSSFP. All images were reconstructed with TGRAPPA. SMS images were also reconstructed using a non-linear iterative reconstruction with L1 regularisation in wavelet space (SMS-iter) with 7 different combinations for spatial (λσ) and temporal (λτ) regularisation parameters. Qualitative ratings of overall image quality (0 = poor image quality, 1 = major artifact, 2 = minor artifact, 3 = excellent), perceived SNR (0 = poor SNR, 1 = major noise, 2 = minor noise, 3 = high SNR), frequency of sequence related artifacts and patient related artifacts were undertaken. Quantitative analysis of contrast ratio (CR) and percentage of dark rim artifact (DRA) was performed. RESULTS: Among all SMS-iter reconstructions, SMS-iter 6 (λσ 0.001 λτ 0.005) was identified as the optimal reconstruction with the highest overall image quality, least sequence related artifact and higher perceived SNR. SMS-iter 6 had superior overall image quality (2.50 ± 0.53 vs 1.50 ± 0.53, p = 0.005) and perceived SNR (2.25 ± 0.46 vs 0.75 ± 0.46, p = 0.010) compared to 3 slice bSSFP. There were no significant differences in sequence related artifact, CR (3.62 ± 0.39 vs 3.66 ± 0.65, p = 0.88) or percentage of DRA (5.25 ± 6.56 vs 4.25 ± 4.30, p = 0.64) with SMS-iter 6 compared to 3 slice bSSFP. CONCLUSIONS: SMS bSSFP with GC-LOLA and iterative reconstruction improved image quality compared to a 3 slice bSSFP with doubled spatial coverage and preserved in-plane spatial resolution. Future evaluation in patients with coronary artery disease is warranted.

Importance of operator training and rest perfusion on the diagnostic accuracy of stress perfusion cardiovascular magnetic resonance.

BACKGROUND: Clinical evaluation of stress perfusion cardiovascular magnetic resonance (CMR) is currently based on visual assessment and has shown high diagnostic accuracy in previous clinical trials, when performed by expert readers or core laboratories. However, these results may not be generalizable to clinical practice, particularly when less experienced readers are concerned. Other factors, such as the level of training, the extent of ischemia, and image quality could affect the diagnostic accuracy. Moreover, the role of rest images has not been clarified. The aim of this study was to assess the diagnostic accuracy of visual assessment for operators with different levels of training and the additional value of rest perfusion imaging, and to compare visual assessment and automated quantitative analysis in the assessment of coronary artery disease (CAD). METHODS: We evaluated 53 patients with known or suspected CAD referred for stress-perfusion CMR. Nine operators (equally divided in 3 levels of competency) blindly reviewed each case twice with a 2-week interval, in a randomised order, with and without rest images. Semi-automated Fermi deconvolution was used for quantitative analysis and estimation of myocardial perfusion reserve as the ratio of stress to rest perfusion estimates. RESULTS: Level-3 operators correctly identified significant CAD in 83.6% of the cases. This percentage dropped to 65.7% for Level-2 operators and to 55.7% for Level-1 operators (p < 0.001). Quantitative analysis correctly identified CAD in 86.3% of the cases and was non-inferior to expert readers (p = 0.56). When rest images were available, a significantly higher level of confidence was reported (p = 0.022), but no significant differences in diagnostic accuracy were measured (p = 0.34). CONCLUSIONS: Our study demonstrates that the level of training is the main determinant of the diagnostic accuracy in the identification of CAD. Level-3 operators performed at levels comparable with the results from clinical trials. Rest images did not significantly improve diagnostic accuracy, but contributed to higher confidence in the results. Automated quantitative analysis performed similarly to level-3 operators. This is of increasing relevance as recent technical advances in image reconstruction and analysis techniques are likely to permit the clinical translation of robust and fully automated quantitative analysis into routine clinical practice.

Cancer therapy related cardiac dysfunction as a result of Panitumumab.

Panitumumab is a human immunoglobulin monoclonal antibody designed to target the epidermal growth factor receptor (EGFR) which is used in the treatment of metastatic colorectal cancer alone or in combination with chemotherapy. In this report, we present a case of new onset heart failure with reduced ejection fraction in a patient following panitumumab therapy. A 73-year-old gentleman with metastatic rectal adenocarcinoma presented to his local hospital with increased shortness of breath, two months after his first and only dose of panitumumab. A transthoracic echocardiogram demonstrated dilated left ventricle with global hypokinesis and an estimated left ventricular ejection fraction of 25%. Our patient underwent a comprehensive diagnostic assessment at his presentation, including ECG, transthoracic echocardiogram, cardiac magnetic resonance, computed tomography coronary angiography (CTCA), invasive coronary angiogram and 18F-FDG PET-CT. These investigations revealed no evidence of ischemic events or inflammatory processes that could account for the severe left ventricular dysfunction. To our knowledge, this is the first reported case of heart failure with reduced ejection fraction linked to panitumumab with subsequent deep phenotyping. The current guidelines do not recommend specific cardiovascular monitoring protocols for patients receiving anti-EGFR monoclonal antibodies. Until more data are available, it would be prudent to implement the same cardiovascular surveillance measures outlined for individuals receiving osimertinib, which is an EGFR tyrosine kinase inhibitor.

Late cardiotoxicity related to HER2-targeted cancer therapy.

Long-term anti-HER2 therapy in metastatic HER2 + cancers is increasing, but data about the incidence and risk factors for developing late Cancer therapy-related cardiac dysfunction (CTRCD) are missing. We conducted a single-centre, retrospective analysis of a cohort of late anti-HER2 related cardiac dysfunction referred to our Cardio-Oncology service. We include seventeen patients with metastatic disease who developed CTRCD after at least five years of continuous anti-HER2 therapy. Events occurred after a median time of 6.5 years (IQR 5.3-9.0) on anti-HER2 therapy. The lowest (median) LVEF and GLS were 49% (IQR 45-55) and - 15.4% (IQR - 14.9 - -16.3) respectively. All our patients continued or restarted, after a brief interruption, their anti-HER2 therapy. Most (16/17) were started on heart failure medical therapy and normalized their left ventricular ejection fraction at a follow-up. Our study has demonstrated that CTRCD can occur after many years of stability on anti-HER2 therapy and reinforces the importance of continuing cardiovascular surveillance in this population.

Complementary use of cardiac magnetic resonance and 18 F-FDG positron emission tomography imaging in suspected immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI) myocarditis is an uncommon but potentially fatal complication of immunotherapy. Cardiac imaging is essential to make timely diagnoses as there are critical downstream implications for patients. OBJECTIVE: To determine the agreement of cardiac magnetic resonance (CMR) and 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in patients with suspected ICI myocarditis. METHODS: Patients with suspected ICI myocarditis, who underwent CMR and 18 F-FDG-PET imaging at a single cardio-oncology service from 2017 to 2023, were enrolled. CMR was performed according to recommended guidelines for assessment of myocarditis. 18 F-FDG-PET imaging was performed following 18 h carbohydrate-free fast. Imaging was analysed by independent reviewers to determine the presence or absence of ICI myocarditis. RESULTS: Twelve patients (mean age 60 ± 15 years old, 7 [58%] male) underwent both CMR and 18 F-FDG-PET imaging. Three (25%) met the 2018 Lake Louise Criteria for CMR diagnosis of myocarditis; 4 (33%) had evidence of myocardial inflammation as determined by 18 F-FDG-PET. Amongst those with positive 18 F-FDG-PET, mean standard uptake value (SUV) was 3.5 ± 1.7. There was agreement between CMR and PET in 7 cases (CMR and PET positive (n = 1), CMR and PET negative (n = 6)) and discordance in 5 cases (CMR positive and PET negative (n = 2), CMR negative and PET positive (n = 3)). CONCLUSION: Both CMR and PET provide complementary clinical information in diagnostic of ICI myocarditis. CMR informs on myocardial oedema, whilst 18 F-FDG-PET provides information on glucose metabolism reflecting monocyte and lymphocytic activity. Future studies should investigate the role of hybrid PET-CMR for the timely diagnosis of ICI myocarditis.