Diffuse myocardial fibrosis precedes subclinical functional myocardial impairment and provides prognostic information in systemic sclerosis.

AIMS: Myocardial involvement is common in patients with systemic sclerosis (SSc) and causes myocardial fibrosis and subtle ventricular dysfunction. However, the temporal onset of myocardial involvement during the progression of the disease and its prognostic value are yet unknown. We used cardiovascular magnetic resonance (CMR) to investigate subclinical functional impairment and diffuse myocardial fibrosis in patients with very early diagnosis of SSc (VEDOSS) and established SSc and examined whether this was associated with mortality. METHODS AND RESULTS: One hundred and ten SSc patients (86 established SSc, 24 VEDOSS) and 15 healthy controls were prospectively recruited. The patients were followed-up for a median duration of 7.0 years (interquartile range 6.0-7.3 years). Study subjects underwent CMR including assessment of myocardial fibrosis [native T1 and extracellular volume (ECV)] and measurement of global longitudinal (GLS) and circumferential (GCS) myocardial strain. Native T1 values and ECV were elevated in VEDOSS and SSc patients compared with controls (P < 0.001). GLS was similar in VEDOSS and controls but significantly impaired in patients with established SSc (P < 0.001). GCS was similar over all groups (P = 0.88). There were 12 deaths during follow-up. Elevated native T1 [hazard ratio (HR) 5.8, 95% confidence interval (CI): 1.7-20.4; P = 0.006] and reduced GLS (HR 6.1, 95% CI: 1.3-29.9; P = 0.038) identified subjects with increased risk of death. Only native T1 was predictive for cardiovascular mortality (P < 0.001). CONCLUSION: Subclinical myocardial involvement first manifests as diffuse myocardial fibrosis identified by the expansion of ECV and increased native T1 in VEDOSS patients while subtle functional impairment only occurs in established SSc. Native T1 and GLS have prognostic value for all-cause mortality in SSc patients.

Multi-centre study of whole-heart dynamic 3D cardiac magnetic resonance perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve: gender based analysis of diagnostic performance.

AIMS: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in women and non-invasive testing for CAD in women can be more challenging than in men. This study compared the diagnostic performance of whole-heart dynamic 3D cardiovascular magnetic resonance (CMR) stress perfusion imaging in female and male patients with quantitative coronary angiography (QCA) and fractional flow reserve (FFR) as reference tests. METHODS AND RESULTS: Four hundred sixteen patients with suspected or known CAD were enrolled in five European centres. CMR imaging was performed prior to clinically indicated coronary angiography. QCA was performed in all patients and FFR in 357 of 416 patients. Whole-heart dynamic 3D CMR first-pass perfusion imaging was conducted at rest and during adenosine stress. All CMR analyses were operated by experienced investigators blinded to all clinical data. One hundred nineteen female and 297 male patients were included and successfully examined (mean age 65 ± 11 and 63 ± 11 years, respectively). FFR was performed in 106 female and 251 male patients. Sensitivity and specificity of whole-heart dynamic 3D CMR stress perfusion imaging were 89% (95% CI: 77-96) and 82% (95% CI: 70-90) in the female population and 83% (95% CI: 77-86) and 79% (95% CI: 71-86) in the male population relative to QCA (P = 0.474 and P = 0.83, P-values for comparison between genders). Sensitivity and specificity were 95% (95% CI: 82-99) and 84% (95% CI: 73-92) in the female population and 83% (95% CI: 76-89) and 82% (95% CI: 74-88) in the male population when using FFR as the reference (P = 0.134 and P = 0.936, P-values for comparison between genders). Diagnostic accuracy in females was 92% (95% CI: 85-96) and 86% (95% CI: 81-90) in males when using FFR as the reference. The prevalence of CAD as defined by FFR (<0.8) was 36% in females and 53% in males. CONCLUSION: Whole-heart dynamic 3D CMR stress perfusion imaging has a high diagnostic accuracy for the detection of significant CAD irrespective of gender and is therefore a suitable non-invasive testing tool to detect myocardial ischaemia in both genders.

Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity-selective excitation.

BACKGROUND: A velocity-selective binomial excitation scheme for myocardial first-pass perfusion measurements with hyperpolarized 13C substrates, which preserves bolus magnetization inside the blood pool, is presented. The proposed method is evaluated against gadolinium-enhanced 1H measurements in-vivo. METHODS: The proposed excitation with an echo-planar imaging readout was implemented on a clinical CMR system. Dynamic myocardial stress perfusion images were acquired in six healthy pigs after bolus injection of hyperpolarized 13C urea with the velocity-selective vs. conventional excitation, as well as standard 1H gadolinium-enhanced images. Signal-to-noise, contrast-to-noise (CNR) and homogeneity of semi-quantitative perfusion measures were compared between methods based on first-pass signal-intensity time curves extracted from a mid-ventricular slice. Diagnostic feasibility is demonstrated in a case of septal infarction. RESULTS: Velocity-selective excitation provides over three-fold reduction in blood pool signal with a two-fold increase in myocardial CNR. Extracted first-pass perfusion curves reveal a significantly reduced variability of semi-quantitative first-pass perfusion measures (12-20%) for velocity-selective excitation compared to conventional excitation (28-93%), comparable to that of reference 1H gadolinium data (9-15%). Overall image quality appears comparable between the velocity-selective hyperpolarized and gadolinium-enhanced imaging. CONCLUSION: The feasibility of hyperpolarized 13C first-pass perfusion CMR has been demonstrated in swine. Comparison with reference 1H gadolinium data revealed sufficient data quality and indicates the potential of hyperpolarized perfusion imaging for human applications.

Analysis of spatiotemporal fidelity in quantitative 3D first-pass perfusion cardiovascular magnetic resonance.

BACKGROUND: Whole-heart first-pass perfusion cardiovascular magnetic resonance (CMR) relies on highly accelerated image acquisition. The influence of undersampling on myocardial blood flow (MBF) quantification has not been systematically investigated yet. In the present work, the effect of spatiotemporal scan acceleration on image reconstruction accuracy and MBF error was studied using a numerical phantom and validated in-vivo. METHODS: Up to 10-fold scan acceleration using k-t PCA and k-t SPARSE-SENSE was simulated using the MRXCAT CMR numerical phantom framework. Image reconstruction results were compared to ground truth data in the k-f domain by means of modulation transfer function (MTF) analysis. In the x-t domain, errors pertaining to specific features of signal intensity-time curves and MBF values derived using Fermi model deconvolution were analysed. In-vivo first-pass CMR data were acquired in ten healthy volunteers using a dual-sequence approach assessing the arterial input function (AIF) and myocardial enhancement. 10x accelerated 3D k-t PCA and k-t SPARSE-SENSE were compared and related to non-accelerated 2D reference images. RESULTS: MTF analysis revealed good recovery of data upon k-t PCA reconstruction at 10x undersampling with some attenuation of higher temporal frequencies. For 10x k-t SPARSE-SENSE the MTF was found to decrease to zero at high spatial frequencies for all temporal frequencies indicating a loss in spatial resolution. Signal intensity-time curve errors were most prominent in AIFs from 10x k-t PCA, thereby emphasizing the need for separate AIF acquisition using a dual-sequence approach. These findings were confirmed by MBF estimation based on AIFs from fully sampled and undersampled simulations. Average in-vivo MBF estimates were in good agreement between both accelerated and the fully sampled methods. Intra-volunteer MBF variation for fully sampled 2D scans was lower compared to 10x k-t PCA and k-t SPARSE-SENSE data. CONCLUSION: Quantification of highly undersampled 3D first-pass perfusion CMR yields accurate MBF estimates provided the AIF is obtained using fully sampled or moderately undersampled scans as part of a dual-sequence approach. However, relative to fully sampled 2D perfusion imaging, intra-volunteer variation is increased using 3D approaches prompting for further developments.

A multisample dissolution dynamic nuclear polarization system for serial injections in small animals.

PURPOSE: Several in vivo applications of dissolution dynamic nuclear polarization (DNP) require rapid successive injections of hyperpolarized substrates. Here we present the design and performance of a custom-built multisample dissolution DNP setup for small animal research. METHODS: The DNP setup consists of a commercial wide-bore magnet charged to 3.35 T, a cryostat, a 94-GHz microwave source, and a custom-built skeleton that accommodates four identical sample sticks. Each sample stick features a dissolver locked into the skeleton port and a lifter, which permits moving the sample cup out of the liquid helium bath for dissolution. RESULTS: The dissolution of the first sample was triggered after 2 hours of polarization buildup during single-shot operation of the cryostat. Thereafter, a time window of 75-90 min was available to dissolve the remaining three polarized samples. The average liquid state polarization over all four sticks was measured as 18.7% ± 2.3% for [1-13C] pyruvate 30 s after dissolution. In vivo applicability of the setup using serial injections of [1-13C] pyruvate to study cardiac metabolism in rats revealed good reproducibility. CONCLUSION: The proposed four-sample DNP insert provides reproducible liquid state polarization of [1-13C] pyruvate and allows for rapid repeat injections in small animals. Magn Reson Med 77:904-910, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Hyperpolarized Metabolic MR Imaging of Acute Myocardial Changes and Recovery after Ischemia-Reperfusion in a Small-Animal Model.

PURPOSE: To implement hyperpolarized magnetic resonance (MR) imaging in an animal model of ischemia-reperfusion and to assess in vivo the regional changes in pyruvate metabolism within the 1st hour and at 1 week after a brief episode of coronary occlusion and reperfusion. MATERIALS AND METHODS: All animal experiments were performed with adherence to the Swiss Animal Protection law and were approved by the regional veterinary office. A closed-chest rat model was implemented by using an inflatable balloon secured around the left coronary artery. Animals were placed in an MR system 5-7 days after surgery. [1-(13)C]pyruvate was polarized by using a home-built multisample hyperpolarizer. Hyperpolarized pyruvate was injected at five stages: at baseline; at reperfusion after 15 minutes of coronary occlusion; and at 30 minutes, 60 minutes, and 1 week after ischemia reperfusion. The conversion of pyruvate into lactate and bicarbonate was imaged by using dedicated MR sequences alongside wall motion and delayed enhancement imaging. After imaging, the heart was removed and stained to delineate the area at risk (AAR). Differences between AAR and remote myocardium were assessed by using a repeated measures analysis of variance and a post hoc Bonferroni multiple comparison test. RESULTS: Data were collected in 12 animals. Occlusion led to hypokinesia of the anterior or anterolateral segments of the myocardium. At reperfusion, the average lactate-to-bicarbonate ratio increased in the AAR relative to that at baseline (from 1.93 ± 0.48 to 3.01 ± 0.74, P < .001) and was significantly higher when compared with that in the remote area (1.91 ± 0.38, P < .001). In the 60 minutes after occlusion, the lactate-to-bicarbonate ratio in the AAR recovered but was still elevated relative to that in the remote area. One week after ischemia-reperfusion, no difference between AAR and remote area could be detected. CONCLUSION: Hyperpolarized metabolic MR imaging can be used to successfully detect acute changes in [1-(13)C]pyruvate metabolism after ischemia-reperfusion, thereby enabling in vivo monitoring of the metabolic effects of reperfusion strategies.

Quantitative three-dimensional myocardial perfusion cardiovascular magnetic resonance with accurate two-dimensional arterial input function assessment.

BACKGROUND: Quantification of myocardial perfusion from first-pass cardiovascular magnetic resonance (CMR) images at high contrast agent (CA) dose requires separate acquisition of blood pool and myocardial tissue enhancement. In this study, a dual-sequence approach interleaving 2D imaging of the arterial input function with high-resolution 3D imaging for myocardial perfusion assessment is presented and validated for low and high CA dose. METHODS: A dual-sequence approach interleaving 2D imaging of the aortic root and 3D imaging of the whole left ventricle using highly accelerated k-t PCA was implemented. Rest perfusion imaging was performed in ten healthy volunteers after administration of a Gadolinium-based CA at low (0.025 mmol/kg b.w.) and high dose (0.1 mmol/kg b.w.). Arterial input functions extracted from the 2D and 3D images were analysed for both doses. Myocardial contrast-to-noise ratios (CNR) were compared across volunteers and doses. Variations of myocardial perfusion estimates between volunteers and across myocardial territories were studied. RESULTS: High CA dose imaging resulted in strong non-linearity of the arterial input function in the 3D images at peak CA concentration, which was avoided when the input function was derived from the 2D images. Myocardial CNR was significantly increased at high dose compared to low dose, with a 2.6-fold mean CNR gain. Most robust myocardial blood flow estimation was achieved using the arterial input function extracted from the 2D image at high CA dose. In this case, myocardial blood flow estimates varied by 24% between volunteers and by 20% between myocardial territories when analysed on a per-volunteer basis. CONCLUSION: Interleaving 2D imaging for arterial input function assessment enables robust quantitative 3D myocardial perfusion imaging at high CA dose.

Multicenter evaluation of dynamic three-dimensional magnetic resonance myocardial perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve.

BACKGROUND: First-pass myocardial perfusion cardiovascular magnetic resonance (CMR) imaging yields high diagnostic accuracy for the detection of coronary artery disease (CAD). However, standard 2D multislice CMR perfusion techniques provide only limited cardiac coverage, and hence considerable assumptions are required to assess myocardial ischemic burden. The aim of this prospective study was to assess the diagnostic performance of 3D myocardial perfusion CMR to detect functionally relevant CAD with fractional flow reserve (FFR) as a reference standard in a multicenter setting. METHODS AND RESULTS: A total of 155 patients with suspected CAD listed for coronary angiography with FFR were prospectively enrolled from 5 European centers. 3D perfusion CMR was acquired on 3T MR systems from a single vendor under adenosine stress and at rest. All CMR perfusion analyses were performed in a central laboratory and blinded to all clinical data. One hundred fifty patients were successfully examined (mean age 62.9±10 years, 45 female). The prevalence of CAD defined by FFR (<0.8) was 56.7% (85 of 150 patients). The sensitivity and specificity of 3D perfusion CMR were 84.7% and 90.8% relative to the FFR reference. Comparison to quantitative coronary angiography (≥50%) yielded a prevalence of 65.3%, sensitivity and specificity of 76.5% and 94.2%, respectively. CONCLUSIONS: In this multicenter study, 3D myocardial perfusion CMR proved highly diagnostic for the detection of significant CAD as defined by FFR.

Hybrid multiband excitation multiecho acquisition for hyperpolarized (13) C spectroscopic imaging.

PURPOSE: Fast dynamic imaging of hyperpolarized (13) C-labeled pyruvate and its downstream metabolites shows great potential for probing metabolic changes in the heart. Sequences that allow for fast encoding of the spectral and spatial information of the myocardial metabolism and optimal signal excitation are usually limited by gradient performance, especially at high magnetic fields. Here we propose a combination of a spectral-spatial multiband excitation and multiecho readout to overcome these limitations. METHODS: By using a low-bandwidth, two-pulse excitation, a thinner slice compared with conventional spectral-spatial excitation is achieved, while at the same time allowing for low flip angle excitation on pyruvate and high flip angle excitation on bicarbonate and lactate, which optimizes signal-to-noise ratio (SNR) in cardiac metabolic imaging. The implementation was evaluated in 13 healthy female Sprague-Dawley rats at 9.4T. RESULTS: Using a slice thickness of 4 mm, a mean (± standard deviation) peak SNR of 18.3 (±8.4), 15.2 (±6.6), and 8.6 (±2.0) was observed for pyruvate, lactate, and bicarbonate, respectively. CONCLUSION: This approach provides high SNR in metabolic images while at the same time allowing for a thin slice selection even at high magnetic fields. This is crucial in metabolic imaging in small animal models.

MRXCAT: Realistic numerical phantoms for cardiovascular magnetic resonance.

BACKGROUND: Computer simulations are important for validating novel image acquisition and reconstruction strategies. In cardiovascular magnetic resonance (CMR), numerical simulations need to combine anatomical information and the effects of cardiac and/or respiratory motion. To this end, a framework for realistic CMR simulations is proposed and its use for image reconstruction from undersampled data is demonstrated. METHODS: The extended Cardiac-Torso (XCAT) anatomical phantom framework with various motion options was used as a basis for the numerical phantoms. Different tissue, dynamic contrast and signal models, multiple receiver coils and noise are simulated. Arbitrary trajectories and undersampled acquisition can be selected. The utility of the framework is demonstrated for accelerated cine and first-pass myocardial perfusion imaging using k-t PCA and k-t SPARSE. RESULTS: MRXCAT phantoms allow for realistic simulation of CMR including optional cardiac and respiratory motion. Example reconstructions from simulated undersampled k-t parallel imaging demonstrate the feasibility of simulated acquisition and reconstruction using the presented framework. Myocardial blood flow assessment from simulated myocardial perfusion images highlights the suitability of MRXCAT for quantitative post-processing simulation. CONCLUSION: The proposed MRXCAT phantom framework enables versatile and realistic simulations of CMR including breathhold and free-breathing acquisitions.

Iterative k-t principal component analysis with nonrigid motion correction for dynamic three-dimensional cardiac perfusion imaging.

PURPOSE: In this study, an iterative k-t principal component analysis (PCA) algorithm with nonrigid frame-to-frame motion correction is proposed for dynamic contrast-enhanced three-dimensional perfusion imaging. METHODS: An iterative k-t PCA algorithm was implemented with regularization using training data corrected for frame-to-frame motion in the x-pc domain. Motion information was extracted using shape-constrained nonrigid image registration of the composite of training and k-t undersampled data. The approach was tested for 10-fold k-t undersampling using computer simulations and in vivo data sets corrupted by respiratory motion artifacts owing to free-breathing or interrupted breath-holds. Results were compared to breath-held reference data. RESULTS: Motion-corrected k-t PCA image reconstruction resolved residual aliasing. Signal intensity curves extracted from the myocardium were close to those obtained from the breath-held reference. Upslopes were found to be more homogeneous in space when using the k-t PCA approach with motion correction. CONCLUSIONS: Iterative k-t PCA with nonrigid motion correction permits correction of respiratory motion artifacts in three-dimensional first-pass myocardial perfusion imaging.

Accelerating hyperpolarized metabolic imaging of the heart by exploiting spatiotemporal correlations.

Hyperpolarized (13)C-labeled pyruvate is a promising tool to investigate cardiac metabolism. It has been shown that changes in substrate metabolism occur following the induction of ischemia. To investigate the metabolic changes that are confined to spatial regions, high spatiotemporal resolution is required. The present work exploits both spatial and temporal correlations using k-t principal component analysis (PCA) to undersample the spatiotemporal domain, thereby speeding up data acquisition. A numerical model was implemented to investigate optimal acquisition and reconstruction parameters for pyruvate, lactate and bicarbonate maps of the heart. Subsequently, prospectively undersampled in vivo data on rat hearts were acquired using a combination of spectral-spatial signal excitation and a variable-density single-shot echo planar readout. Using five-fold k-t PCA, a spatial resolution of 1 × 1 mm(2) at a temporal resolution of 3 s was achieved.

Reconstruction of divergence-free velocity fields from cine 3D phase-contrast flow measurements.

Three-dimensional phase-contrast velocity vector field mapping shows great potential for clinical applications; however measurement inaccuracies may limit the utility and robustness of the technique. While parts of the error in the measured velocity fields can be minimized by background phase estimation in static tissue and magnetic field monitoring, considerable inaccuracies remain. The present work introduces divergence-reduction processing of 3D phase-contrast flow data based on a synergistic combination of normalized convolution and divergence-free radial basis functions. It is demonstrated that this approach effectively addresses erroneous flow for image reconstructions from both fully sampled and undersampled data. Using computer simulations and in vivo data acquired in the aorta of healthy subjects and a stenotic valve patient it is shown that divergence arising from measurement imperfections can be reduced by up to 87% resulting in improved vector field representations. Based on the results obtained it is concluded that integration of the divergence-free condition into postprocessing of vector fields presents an efficient approach to addressing flow field inaccuracies.

Whole-heart dynamic three-dimensional magnetic resonance perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve: determination of volumetric myocardial ischaemic burden and coronary lesion location.

AIMS: Dynamic three-dimensional-cardiac magnetic resonance (3D-CMR) perfusion proved highly diagnostic for the detection of angiographically defined coronary artery disease (CAD) and has been used to assess the efficacy of coronary stenting procedures. The present study aimed to relate significant coronary lesions as assessed by fractional flow reserve (FFR) to the volume of myocardial hypoenhancement on 3D-CMR adenosine stress perfusion imaging and to define the inter-study reproducibility of stress inducible 3D-CMR hypoperfusion. METHODS AND RESULTS: A total of 120 patients with known or suspected CAD were examined in two CMR centres using 1.5 T systems. The protocol included cine imaging, 3D-CMR perfusion during adenosine infusion, and at rest followed by delayed enhancement (DE) imaging. Fractional flow reserve was recorded in epicardial coronary arteries and side branches with ≥2 mm luminal diameter and >40% severity stenosis (pathologic FFR < 0.75). Twenty-five patients underwent an identical repeat CMR examination for the determination of inter-study reproducibility of 3D-CMR perfusion deficits induced by adenosine. Three-dimensional CMR perfusion scans were visually classified as pathologic if one or more segments showed an inducible perfusion deficit in the absence of DE. Myocardial ischaemic burden (MIB) was measured by segmentation of the area of inducible hypoenhancement and normalized to left ventricular myocardial volume (MIB, %). Three-dimensional CMR perfusion resulted in a sensitivity, specificity, and diagnostic accuracy of 90, 82, and 87%, respectively. Substantial concordance was found for inter-study reproducibility [Lin's correlation coefficient: 0.98 (95% confidence interval: 0.96-0.99)]. CONCLUSION: Three-dimensional CMR stress perfusion provided high diagnostic accuracy for the detection of functionally significant CAD. Myocardial ischaemic burden measurements were highly reproducible and allowed the assessment of CAD severity.