ECG-free cine MRI with data-driven clustering of cardiac motion for quantification of ventricular function.

BACKGROUND: Despite the widespread use of cine MRI for evaluation of cardiac function, existing real-time methods do not easily enable quantification of ventricular function. Moreover, segmented cine MRI assumes periodicity of cardiac motion. We aim to develop a self-gated, cine MRI acquisition scheme with data-driven cluster-based binning of cardiac motion. METHODS: A Cartesian golden-step balanced steady-state free precession sequence with sorted k-space ordering was designed. Image data were acquired with breath-holding. Principal component analysis and k-means clustering were used for binning of cardiac phases. Cluster compactness in the time dimension was assessed using temporal variability, and dispersion in the spatial dimension was assessed using the Calinski-Harabasz index. The proposed and the reference electrocardiogram (ECG)-gated cine methods were compared using a four-point image quality score, SNR and CNR values, and Bland-Altman analyses of ventricular function. RESULTS: A total of 10 subjects with sinus rhythm and 8 subjects with arrhythmias underwent cardiac MRI at 3.0 T. The temporal variability was 45.6 ms (cluster) versus 24.6 ms (ECG-based) (p < 0.001), and the Calinski-Harabasz index was 59.1 ± 9.1 (cluster) versus 22.0 ± 7.1 (ECG based) (p < 0.001). In subjects with sinus rhythm, 100% of the end-systolic and end-diastolic images from both the cluster and reference approach received the highest image quality score of 4. Relative to the reference cine images, the cluster-based multiphase (cine) image quality consistently received a one-point lower score (p < 0.05), whereas the SNR and CNR values were not significantly different (p = 0.20). In cases with arrhythmias, 97.9% of the end-systolic and end-diastolic images from the cluster approach received an image quality score of 3 or more. The mean bias values for biventricular ejection fraction and volumes derived from the cluster approach versus reference cine were negligible. CONCLUSION: ECG-free cine cardiac MRI with data-driven clustering for binning of cardiac motion is feasible and enables quantification of cardiac function.

Fractional myocardial blood volume by ferumoxytol-enhanced MRI: Estimation of ischemic burden.

PURPOSE: To investigate model-fitted fractional myocardial blood volume (fMBV) derived from ferumoxytol-enhanced MRI as a measure of myocardial tissue hypoperfusion at rest. METHODS: We artificially induced moderate to severe focal coronary stenosis in the left anterior descending artery of 19 swine by percutaneous delivery of a 3D-printed coronary implant. Using the MOLLI pulse sequence, we acquired T1 maps at 3 T after multiple incremental ferumoxytol doses (0.0-4.0 mg/kg). We computed pixel-wise fMBV using a multi-compartmental modeling approach in 19 ischemic swine and 4 healthy swine. RESULTS: Ischemic myocardial segments showed a mean MRI-fMBV of 11.72 ± 3.00%, compared with 8.23 ± 2.12% in remote segments and 8.38 ± 2.23% in normal segments. Ischemic segments showed a restricted transvascular water-exchange rate (ki  = 15.32 ± 8.69 s-1 ) relative to remote segments (ki  = 17.78 [11.60, 26.36] s-1 ). A mixed-effects model found significant difference in fMBV (p = 0.002) and water-exchange rate (p < 0.001) between ischemic and remote myocardial regions after adjusting for biological sex and slice location. Analysis of fMBV as a predictor of impaired myocardial contractility using receiver operating characteristics showed an area under the curve of 0.89 (95% confidence interval [CI] 0.80, 0.95). An MRI-fMBV threshold of 9.60% has a specificity of 90.0% (95% CI 76.3, 97.2) and a sensitivity of 72.5% (95% CI 56.1, 83.4) for prediction of impaired myocardial contractility. CONCLUSIONS: Model-fitted fMBV derived from ferumoxytol-enhanced MRI can distinguish regions of ischemia from remote myocardium in a swine model of myocardial hypoperfusion.

Comparison of Three Ultrasmall, Superparamagnetic Iron Oxide Nanoparticles for MRI at 3.0 T.

BACKGROUND: The ultrasmall, superparamagnetic iron oxide (USPIO) nanoparticle ferumoxytol has unique applications in cardiac, vascular, and body magnetic resonance imaging (MRI) due to its long intravascular half-life and suitability as a blood pool agent. However, limited availability and high cost have hindered its clinical adoption. A new ferumoxytol generic, and the emergence of MoldayION as an alternative USPIO, represent opportunities to expand the use of USPIO-enhanced MRI techniques. PURPOSE: To compare in vitro and in vivo MRI relaxometry and enhancement of Feraheme, generic ferumoxytol, and MoldayION. STUDY TYPE: Prospective. ANIMAL MODEL: Ten healthy swine and six swine with artificially induced coronary narrowing underwent cardiac MRI. FIELD STRENGTH/SEQUENCE: 3.0 T; T1-weighted (4D-MUSIC, 3D-VIBE, 2D-MOLLI) and T2-weighted (2D-HASTE) sequences pre- and post-contrast. ASSESSMENT: We compared the MRI relaxometry of Feraheme, generic ferumoxytol, and MoldayION using saline, plasma, and whole blood MRI phantoms with contrast concentrations from 0.26 mM to 2.10 mM. In-vivo contrast effects on T1- and T2-weighted sequences and fractional intravascular contrast distribution volume in myocardium, liver, and spleen were evaluated. STATISTICAL TESTS: Analysis of variance and covariance were used for group comparisons. A P value <0.05 was considered statistically significant. RESULTS: The r1 relaxivities for Feraheme, generic ferumoxytol, and MoldayION in saline (22 °C) were 7.11 ± 0.13 mM-1  s-1 , 8.30 ± 0.29 mM-1  s-1 , 8.62 ± 0.16 mM-1  s-1 , and the r2 relaxivities were 111.74 ± 3.76 mM-1  s-1 , 105.07 ± 2.20 mM-1  s-1 , and 109.68 ± 2.56 mM-1  s-1 , respectively. The relationship between contrast concentration and longitudinal (R1) and transverse (R2) relaxation rate was highly linear in saline and plasma. The three agents produced similar in vivo contrast effects on T1 and T2 relaxation time-weighted sequences. DATA CONCLUSION: Relative to clinically approved ferumoxytol formulations, MoldayION demonstrates minor differences in in vitro relaxometry and comparable in vivo MRI characteristics. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Free-breathing, non-ECG, simultaneous myocardial T1 , T2 , T2 *, and fat-fraction mapping with motion-resolved cardiovascular MR multitasking.

PURPOSE: To develop a free-breathing, non-electrocardiogram technique for simultaneous myocardial T1 , T2 , T2 *, and fat-fraction (FF) mapping in a single scan. METHODS: The MR Multitasking framework is adapted to quantify T1 , T2 , T2 *, and FF simultaneously. A variable TR scheme is developed to preserve temporal resolution and imaging efficiency. The underlying high-dimensional image is modeled as a low-rank tensor, which allows accelerated acquisition and efficient reconstruction. The accuracy and/or repeatability of the technique were evaluated on static and motion phantoms, 12 healthy volunteers, and 3 patients by comparing to the reference techniques. RESULTS: In static and motion phantoms, T1 /T2 /T2 */FF measurements showed substantial consistency (R > 0.98) and excellent agreement (intraclass correlation coefficient > 0.93) with reference measurements. In human subjects, the proposed technique yielded repeatable T1 , T2 , T2 *, and FF measurements that agreed with those from references. CONCLUSIONS: The proposed free-breathing, non-electrocardiogram, motion-resolved Multitasking technique allows simultaneous quantification of myocardial T1 , T2 , T2 *, and FF in a single 2.5-min scan.

Ferumoxytol-enhanced magnetic resonance T1 reactivity for depiction of myocardial hypoperfusion.

Myocardial T1 reactivity, defined as the relative change in T1 between rest and vasodilator-induced stress, has been proposed as a magnetic resonance imaging (MRI) biomarker of tissue perfusion. We hypothesize that the superparamagnetic iron-oxide nanoparticle, ferumoxytol, sensitizes T1 to changes in the intramyocardial vascular compartment and improves the sensitivity and specificity of T1 reactivity as an imaging biomarker of tissue perfusion. We aim to assess the diagnostic performance of ferumoxytol-enhanced (FE) myocardial T1 reactivity in swine models of myocardial hypoperfusion. We induced acute myocardial hypoperfusion in 13 swine via percutaneous, transcatheter deployment of a 3D printed intracoronary stenosis implant into the left anterior descending coronary artery. We performed native and FE adenosine stress testing using 5(3)3(3)3 MOLLI and SASHA T1 mapping sequences with bSSFP readout on a clinical 3.0 T magnet. MOLLI T1 maps were fitted using both the conventional MOLLI and the Instantaneous Signal Loss (InSiL) T1-fitting algorithms. Regardless of the MOLLI or SASHA pulse sequence or T1-fitting algorithm, ferumoxytol contrast increased the dynamic range of T1 reactivity in both the remote and ischemic myocardial regions. Relative to remote myocardium, native and FE T1 reactivity were blunted in ischemic myocardium (p < 0.05) with InSiL-MOLLI, MOLLI and SASHA. An InSiL-MOLLI-derived FE T1 reactivity threshold of -4.65% had 73.3% sensitivity and 96.2% specificity for prediction of regional wall motion abnormalities (AUC 0.915, 95% CI 0.786-0.979), whereas a SASHA-derived FE T1 reactivity threshold of -5.25% had 75.0% sensitivity and 95.2% specificity (AUC 0.905, 95% CI 0.751-0.979). Ferumoxytol significantly increased the dynamic range of T1 reactivity as a measure of myocardial hypoperfusion in vasodilator stress T1 mapping studies. FE T1 reactivity maps can be used to quantitatively distinguish ischemic and remote myocardium with high specificity in swine models of acute myocardial hypoperfusion.

Estimation of fractional myocardial blood volume and water exchange using ferumoxytol-enhanced magnetic resonance imaging.

Fractional myocardial blood volume (fMBV) estimated using ferumoxytol-enhanced magnetic resonance imaging (MRI) (FE-MRI) has the potential to capture a hemodynamic response to myocardial hypoperfusion during contrast steady state without reliance on gadolinium chelates. Ferumoxytol has a long intravascular half-life and its use for steady-state MRI is off-label. The aim of this prospective study was to optimize and evaluate a two-compartment model for estimation of fMBV based on FE-MRI. Nine healthy swine and one swine with artificially induced single-vessel coronary stenosis underwent MRI on a 3.0 T clinical magnet. Myocardial longitudinal spin-lattice relaxation rate (R1) was measured using the 5(3)3(3)3 modified Look-Locker inversion recovery (MOLLI) sequence before and at contrast steady state following seven ferumoxytol infusions (0.125-4.0 mg/kg). fMBV and water exchange were estimated using a two-compartment model. Model-fitted fMBV was compared to simple fast-exchange fMBV approximation and percent change in pre- and postferumoxytol R1. Dose undersampling schemes were investigated to reduce acquisition duration. Variation in fMBV was assessed using one-way analysis of variance. Fast-exchange fMBV and ferumoxytol dose undersampling were evaluated using Bland-Altman analysis. Healthy normal swine showed a mean mid-ventricular fMBV of 7.2 ± 1.4% and water exchange rate of 11.3 ± 5.1 s-1 . There was intersubject variation in fMBV (p < 0.05) without segmental variation (p = 0.387). fMBV derived from eight-dose and four-dose sampling schemes had no significant bias (mean difference = 0.07, p = 0.541, limits of agreement -1.04% [-1.45, -0.62%] to 1.18% [0.77, 1.59%]). Pixel-wise fMBV in one swine model with coronary artery stenosis showed elevated fMBV in ischemic segments (apical anterior: 11.90 ± 4.00%, apical septum: 16.10 ± 5.71%) relative to remote segments (apical inferior: 9.59 ± 3.35%, apical lateral: 9.38 ± 2.35%). A two-compartment model based on FE-MRI using the MOLLI sequence may enable estimation of fMBV in studies of ischemic heart disease. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

Volumetric-modulated arc therapy using multicriteria optimization for body and extremity sarcoma.

This study evaluates the implementation of volumetric-modulated arc therapy (VMAT) using multicriteria optimization (MCO) in the RayStation treatment planning system (TPS) for complex sites, namely extremity and body sarcoma. The VMAT-MCO algorithm implemented in RayStation is newly developed and requires an integrated, comprehensive analysis of plan generation, delivery, and treatment efficiency. Ten patients previously treated by intensity-modulated radiation therapy (IMRT) with MCO were randomly selected and replanned using VMAT-MCO. The plan quality was compared using homogeneity index (HI) and conformity index (CI) of the planning target volume (PTV) and dose sparing of organs at risk (OARs). Given the diversity of the tumor location, the 10 plans did not have a common OAR except for skin. The skin D50 and Dmean was directly compared between VMAT-MCO and IMRT-MCO. Additional OAR dose points were compared on a plan-by-plan basis. The treatment efficiency was compared using plan monitor units (MU) and net beam-on time. Plan quality assurance was performed using the Sun Nuclear ArcCHECK phantom and a gamma criteria of 3%/3 mm. No statistically significant differences were found between VMAT- and IMRT-MCO for HI and CI of the PTV or D50 and Dmean to the skin. The VMAT-MCO plans showed general improvements in sparing to OARs. The VMAT-MCO plan set showed statistically significant improvements over the IMRT-MCO set in treatment efficiency per plan MU (p < 0.05) and net beam-on time (p < 0.01). The VMAT-MCO plan deliverability was validated. Similar gamma passing rates were observed for the two modalities. This study verifies the suitability of VMAT-MCO for sarcoma cancer and highlighted the comparability in plan quality and improve-ment in treatment efficiency offered by VMAT-MCO as compared to IMRT-MCO.

Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease.

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally (3D) printed coronary implants can be employed to percutaneously create a focal coronary stenosis. However, reliable delivery of the implants can be difficult without the use of ancillary equipment. We describe the use of a mother-and-child coronary guide catheter for stabilization of the implant and for effective delivery of the 3D printed implant to any desired location along the length of the coronary vessel. The focal coronary narrowing was confirmed under coronary cineangiography and the functional significance of the coronary stenosis was assessed using gadolinium-enhanced first-pass cardiac perfusion MRI. We showed that reliable delivery of 3D printed coronary implants in swine models (n = 11) of ischemic heart disease can be achieved through repurposing mother-and-child coronary guide catheters. Our technique simplifies the percutaneous delivery of coronary implants to create closed-chest swine models of focal coronary artery stenosis and can be performed expeditiously, with a low procedural failure rate.

3D-Printed Coronary Implants Are Effective for Percutaneous Creation of Swine Models with Focal Coronary Stenosis.

Reliable, closed-chest methods for creating large animal models of acute myocardial hypoperfusion are limited. We demonstrated the feasibility and efficacy of using magnetic resonance (MR)-compatible 3D-printed coronary implants for establishing swine models of myocardial hypoperfusion. We designed, manufactured, and percutaneously deployed implants in 13 swine to selectively create focal coronary stenosis. To test the efficacy of the implants to cause hypoperfusion or ischemia in the perfused territory, we evaluated regional wall motion, myocardial perfusion, and infarction using MR imaging. The overall swine survival rate was 85% (11 of 13). The implant retrieval rate was 92% (12 of 13). Fluoroscopic angiography confirmed focal stenosis. Cine and perfusion MRI showed regional wall motion abnormalities and inducible ischemia, respectively. Late gadolinium enhancement and histopathology showed no myocardial infarction. Our minimally invasive technique has promising applications for validation of new diagnostic methods in cardiac MR. Graphical abstract Our new minimally invasive, percutaneous method for creating swine models of acute focal coronary stenosis can be used for magnetic resonance imaging studies of myocardial ischemia. Comparable to existing methods in its efficacy and reliability, this rapid prototyping technique will allow researchers to more easily conduct translational cardiac imaging studies of coronary artery disease in large animal models.