Estimating the arterial input function from dynamic contrast-enhanced MRI data with compensation for flow enhancement (II): Applications in spine diagnostics and assessment of crohn's disease.

BACKGROUND: Pharmacokinetic (PK) models can describe microvascular density and integrity. An essential component of PK models is the arterial input function (AIF) representing the time-dependent concentration of contrast agent (CA) in the blood plasma supplied to a tissue. PURPOSE/HYPOTHESIS: To evaluate a novel method for subject-specific AIF estimation that takes inflow effects into account. STUDY TYPE: Retrospective study. SUBJECTS: Thirteen clinical patients referred for spine-related complaints; 21 patients from a study into luminal Crohn's disease with known Crohn's Disease Endoscopic Index of Severity (CDEIS). FIELD STRENGTH/SEQUENCE: Dynamic fast spoiled gradient echo (FSPGR) at 3T. ASSESSMENT: A population-averaged AIF, AIFs derived from distally placed regions of interest (ROIs), and the new AIF method were applied. Tofts' PK model parameters (including vp and Ktrans ) obtained with the three AIFs were compared. In the Crohn's patients Ktrans was correlated to CDEIS. STATISTICAL TESTS: The median values of the PK model parameters from the three methods were compared using a Mann-Whitney U-test. The associated variances were statistically assessed by the Brown-Forsythe test. Spearman's rank correlation coefficient was computed to test the correlation of Ktrans to CDEIS. RESULTS: The median vp was significantly larger when using the distal ROI approach, compared to the two other methods (P < 0.05 for both comparisons, in both applications). Also, the variances in vp were significantly larger with the ROI approach (P < 0.05 for all comparisons). In the Crohn's disease study, the estimated Ktrans parameter correlated better with the CDEIS (r = 0.733, P < 0.001) when the proposed AIF was used, compared to AIFs from the distal ROI method (r = 0.429, P = 0.067) or the population-averaged AIF (r = 0.567, P = 0.011). DATA CONCLUSION: The proposed method yielded realistic PK model parameters and improved the correlation of the Ktrans parameter with CDEIS, compared to existing approaches. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2018;47:1197-1204.

MRI protocol optimization for quantitative DCE-MRI of the spine.

PURPOSE: In this study we systematically investigated different Dynamic Contrast Enhancement (DCE)-MRI protocols in the spine, with the goal of finding an optimal protocol that provides data suitable for quantitative pharmacokinetic modelling (PKM). MATERIALS AND METHODS: In 13 patients referred for MRI of the spine, DCE-MRI of the spine was performed with 2D and 3D MRI protocols on a 3T Philips Ingenuity MR system. A standard bolus of contrast agent (Dotarem - 0.2ml/kg body weight) was injected intravenously at a speed of 3ml/s. Different techniques for acceleration and motion compensation were tested: parallel imaging, partial-Fourier imaging and flow compensation. The quality of the DCE MRI images was scored on the basis of SNR, motion artefacts due to flow and respiration, signal enhancement, quality of the T1 map and of the arterial input function, and quality of pharmacokinetic model fitting to the extended Tofts model. RESULTS: Sagittal 3D sequences are to be preferred for PKM of the spine. Acceleration techniques were unsuccessful due to increased flow or motion artefacts. Motion compensating gradients failed to improve the DCE scans due to the longer echo time and the T2* decay which becomes more dominant and leads to signal loss, especially in the aorta. The quality scoring revealed that the best method was a conventional 3D gradient-echo acquisition without any acceleration or motion compensation technique. The priority in the choice of sequence parameters should be given to reducing echo time and keeping the dynamic temporal resolution below 5s. Increasing the number of acquisition, when possible, helps towards reducing flow artefacts. In our setting we achieved this with a sagittal 3D slab with 5 slices with a thickness of 4.5mm and two acquisitions. CONCLUSION: The proposed DCE protocol, encompassing the spine and the descending aorta, produces a realistic arterial input function and dynamic data suitable for PKM.

ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE study).

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM. METHODS: Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group. ENDPOINTS: Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.

First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging.

BACKGROUND: Both bevacizumab and erlotinib have clinical activity in non-small-cell lung cancer (NSCLC). Preclinical data suggest synergistic activity. PATIENTS AND METHODS: Chemonaive patients with stage IIIb or IV non-squamous NSCLC were treated with bevacizumab 15 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Primary end point was non-progression rate (NPR) at 6 weeks. Tumor response was measured with computed tomography, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). KRAS and EGFR mutations were assessed in tumor samples. RESULTS: Forty-seven patients were included. Median follow-up was 15.2 months. NPR at 6 weeks was 75%. Median progression-free survival (PFS) was 3.8 [95% confidence interval (CI) 2.3-5.4] months and median overall survival (OS) was 6.9 (95% CI 5.5-8.4) months. Toxicity was mainly mild. The presence of KRAS (n = 10) or EGFR mutations (n = 5) did not influence outcome. After 3 weeks of treatment, >20% decrease in standard uptake value as measured with positron emission tomography predicted for longer PFS (9.7 versus 2.8 months; P = 0.01) and >40% decrease in K(trans) as assessed by DCE-MRI did not predict for longer PFS. CONCLUSIONS: First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG-PET is the best predictive test for PFS.

RC time constant of single lung equals that of both lungs together: a study in chronic thromboembolic pulmonary hypertension.

The product of resistance, R, and compliance, C (RC time), of the entire pulmonary circulation is constant. It is unknown if this constancy holds for individual lungs. We determined R and C in individual lungs in chronic thromboembolic pulmonary hypertension (CTEPH) patients where resistances differ between both lungs. Also, the contribution of the proximal pulmonary arteries (PA) to total lung compliance was assessed. Patients (n=23) were referred for the evaluation of CTEPH. Pressure was measured by right heart catheterization and flows in the main, left, and right PA by magnetic resonance imaging. Total, left, and right lung resistances were calculated as mean pressure divided by mean flow. Total, left, and right lung compliances were assessed by the pulse pressure method. Proximal compliances were derived from cross-sectional area change DeltaA and systolic-diastolic pressure difference DeltaP (DeltaA/DeltaP) in main, left, and right PA, multiplied by vessel length. The lung with the lowest blood flow was defined "low flow" (LF), the contralateral lung "high flow" (HF). Total resistance was 0.57+/-0.28 mmHg.s(-1).ml(-1), and resistances of LF and HF lungs were 1.57+/-0.2 vs. 1.00+/-0.1 mmHg.s(-1).ml(-1), respectively, P<0.0001. Total compliance was 1.22+/-1.1 ml/mmHg, and compliances of LF and HF lung were 0.47+/-0.11 and 0.62+/-0.12 ml/mmHg, respectively, P=0.01. Total RC time was 0.49+/-0.2 s, and RC times for the LF and HF lung were 0.45+/-0.2 and 0.45+/-0.1 s, respectively, not different. Proximal arterial compliance, given by the sum of main, right, and left PA compliances, was only 19% of total lung compliance. The RC time of a single lung equals that of both lungs together, and pulmonary arterial compliance comes largely from the distal vasculature.

Stroke volume increase to exercise in chronic obstructive pulmonary disease is limited by increased pulmonary artery pressure.

AIMS: This study was designed to investigate the mechanisms by which the right ventricle is able to increase stroke volume (SV) during exercise in chronic obstructive pulmonary disease (COPD). A second aim was to determine whether resting pulmonary artery pressure (Ppa) is predictive of exercise SV. METHODS: 16 COPD patients (GOLD stages II-IV) underwent right heart catheterisation at rest and during exercise. In this group and eight age-matched controls resting and exercise right ventricular SV, end-diastolic volume (RVEDV) and end-systolic volume (RVESV) were assessed by magnetic resonance imaging (MRI). The exercise protocol during both measurements consisted of 3 minutes of cycling in supine position at 40% of maximal workload. RESULTS: In all patients mean Ppa increased significantly in response to exercise (21 (8) vs 33 (11) mm Hg, p<0.01), whereas pulmonary vascular resistance did not change. In the patient group, RVEDV (129 (42) vs 135 (42) ml, p<0.05) and SV (63 (13) vs 69 (14) ml, p<0.05) increased significantly from rest to exercise, but RVESV and RV ejection fraction remained unaltered. In contrast, in healthy controls SV is augmented (81 (22) vs 101 (28) ml, p<0.05) by both increased RVEDV (123 (33) vs 134 134) ml, p<0.05) and reduced RVESV (37 (9) vs 27 (10) ml, p<0.05). Resting mean Ppa was related to SV during exercise (r = -0.59, p<0.02). CONCLUSION: As a consequence of unaltered pulmonary vascular resistance to exercise in COPD patients, Ppa increases and SV response to exercise is limited and results from an increased preload only. Ppa at rest predicts exercise SV.

Sildenafil treatment in COPD does not affect stroke volume or exercise capacity.

In chronic obstructive pulmonary disease (COPD) patients, stroke volume response to exercise is impaired. The aim of the present study was to investigate whether 3 months of sildenafil treatment improves stroke volume and, if so, whether this improvement is related to the pulmonary artery pressure and translated into an improved exercise capacity. A total of 15 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) underwent right heart catheterisation at rest and during exercise. Stroke volume was assessed by magnetic resonance imaging (MRI) at rest and during submaximal exercise in the supine position and compared with eight age-matched controls. Additionally, a cardiopulmonary exercise test and a 6-min walking distance test were performed. Exercise tests and MRI were repeated after 12 weeks of oral therapy with 50 mg sildenafil three times daily. Stroke volume in COPD patients was significantly lower than in healthy controls (62+/-12 versus 81+/-22 mL at rest and 70+/-15 versus 101+/-28 mL during exercise). Pulmonary hypertension (PH) was diagnosed in nine patients and was absent in six. Treatment with sildenafil had no effect on stroke volume or exercise capacity. Although the stroke volume was lower in COPD patients with associated PH in comparison with non-PH patients, there was no difference in treatment response between both groups. In the present group of 15 chronic obstructive pulmonary disease patients, a reduced stroke volume was found at rest and during exercise. Neither stroke volume nor exercise capacity were improved by 3 months of sildenafil therapy.

NT-proBNP reflects right ventricular structure and function in pulmonary hypertension.

The aim of the current study was to investigate whether alterations in N-terminal pro brain natriuretic peptide (NT-proBNP) reflect changes in right ventricular structure and function in pulmonary hypertension patients during treatment. The study consisted of 30 pulmonary hypertension patients; 15 newly diagnosed and 15 on long-term treatment. NT-proBNP, right heart catheterisation and cardiac magnetic resonance imaging measurements were performed, at baseline and follow-up. There were no significant differences between newly diagnosed patients and those on treatment at baseline or follow-up with respect to NT-proBNP, haemodynamics and right ventricular parameters. Relative changes in NT-proBNP during treatment were correlated to the relative changes in right ventricular end-diastolic volume index (r = 0.59), right ventricular mass index (r = 0.62) and right ventricular ejection fraction (r = -0.81). N-terminal pro brain natriuretic peptide measurements reflect changes in magnetic resonance imaging-measured right ventricular structure and function in pulmonary hypertension patients. An increase in N-terminal pro brain natriuretic peptide over time reflects right ventricular dilatation concomitant to hypertrophy and deterioration of systolic function.

Noninvasive assessment and monitoring of the pulmonary circulation.

In pulmonary vascular disease, changes in the pulmonary vascular bed will lead to altered pulmonary haemodynamics. This review describes the application of several physiological principles to measure these changes noninvasively by means of novel techniques. Flow characteristics of blood through the pulmonary vascular bed alter in pulmonary vascular disease. Recent developments in magnetic resonance imaging and computed tomography make it possible to visualise and quantify these abnormal flow patterns. Information regarding pulmonary perfusion can also be obtained by measuring the electrical impedance changes in the lung by electrical impedance tomography. A more indirect approach to measure the pulmonary blood flow is the measurement of the absorption of acetylene, a perfusion limited gas. Information on the pulmonary vascular bed can also be obtained by the measurement of exhaled products of the pulmonary vascular endothelium, such as nitric oxide. Although all the techniques described offer new ways to diagnose or monitor pulmonary vascular disease, clinical data on these techniques are limited. Further improvement and evaluation of the clinical value of these techniques are therefore obligatory before they can be used in clinical practice.

Regional timing of myocardial shortening is related to prestretch from atrial contraction: assessment by high temporal resolution MRI tagging in humans.

Earlier studies have shown substantial nonuniformity in normal left ventricular (LV) myocardial function concerning both the degree of shortening and timing of shortening. We hypothesized that nonuniform LV function may be related to nonuniform prestretch induced by atrial contraction. Eleven healthy human subjects were studied using MRI myocardial tagging and strain analysis. The amount of circumferential prestretch was assessed in 30 LV segments. Prestretch was defined as the difference in strain between end diastole (at ECG R wave) and diastasis. Furthermore, both the degree of shortening (quantified as peak circumferential shortening, peak systolic shortening rate, and amount of postsystolic shortening) and timing of shortening (quantified as the onset time of shortening and time to peak shortening) were assessed. LV prestretch was found to be nonuniform, with the highest values in the lateral wall. The amount of segmental prestretch correlated significantly with peak shortening (r = 0.79), peak shortening rate (r = 0.50), amount of postsystolic shortening (r = 0.67), onset time of shortening (r = -0.57), and time to peak shortening (r = 0.71) (P < 0.001 for each of these relations). These relations may be explained by regional differences in wall stress or by a regional Frank-Starling effect. The correlation between timing of shortening and prestretch demonstrates that mechanical timing is not determined by electrical phenomena alone. In conclusion, regional variation in LV function correlates with the nonuniform prestretch from atrial contraction.

Timing of cardiac contraction in humans mapped by high-temporal-resolution MRI tagging: early onset and late peak of shortening in lateral wall.

Mechanical asynchrony is an important parameter in predicting the response to cardiac resynchronization therapy, but detailed knowledge of cardiac contraction timing in healthy persons is scarce. In this work, timing of cardiac contraction was mapped in 17 healthy subjects with high-temporal-resolution (14 ms) MRI myocardial tagging and strain analysis. Both the onset time of circumferential shortening (T(onset)) in early systole and the time of peak circumferential shortening (T(peak)) at end systole were determined. The onset of shortening width (time needed for 20-90% of the left ventricle to start shortening) was small (35 +/- 9 ms). A distinct spatial pattern for T(onset) was found, with earliest onset in the lateral wall and latest onset in the septum (P = 0.001). Compared with T(onset), T(peak) had a larger width (121 +/- 22 ms) and an opposite spatial pattern, with peak shortening occurring earlier in the septum than in the lateral wall (P < 0.001). Postsystolic shortening (T(peak) later than aortic valve closure; P < 0.05) was observed in 13 of the 30 cardiac segments, mainly in the lateral and basal segments. Shortening in these segments continued 58 +/- 14 ms after aortic valve closure, during which circumferential shortening increased from 16.9 +/- 1.2% to 20.0 +/- 1.5%. Maps of the timing of contraction in normal subjects may serve as a reference in detecting mechanical asynchrony due to intraventricular conduction defects or ischemia.

Imaging of thoracic blood volume changes during the heart cycle with electrical impedance using a linear spot-electrode array.

Electrical impedance (EI) measurements conducted on the thorax contain useful information about the changes in blood volume that occur in the thorax during the heart cycle. The aim of this paper is to present a new (tomographic-like) method to obtain this relevant information with electrical impedance measurements, using a linear electrode array. This method is tested on three subjects and the results are compared with results, obtained from magnetic resonance cine-images showing the cross-sectional surface area changes of the aorta, the vena cava, the carotid arteries, and the heart. This paper shows that the different sources of the thoracic EI waveform may be separated in time and location on the thoracic surface and that aortic volume changes may be estimated accurately.

Aortic aneurysm pulsatile wall motion imaged by cine MRI: a tool to evaluate efficacy of endovascular aneurysm repair?

OBJECTIVES: to evaluate cine MRI as a means of determining the two-dimensional pulsatile wall motion (2D-PWM) of abdominal aortic aneurysm (AAA). DESIGN: prospective study of 21 patients with AAA. 2D-PWM was defined as change in cross-sectional area. RESULTS: the median diastolic area was 28 cm(2) (intraquartile range, IQR, 22-31 cm(2)) and the median (IQR) 2D-PWM was 0.25 (0.10-0.40) cm(2). Assuming that the AAA is circular in cross-section this represents a median (IQR) diameter increase of 0.3 (0.1-0.4) mm. However, local wall displacements up to 2 mm were present in varying directions, without significant change in surface area. CONCLUSION: AAA PWM is negligible and may not therefore be a potential tool to assess efficacy of endovascular aneurysm exclusion.

Quantification of regional contractile function after infarction: strain analysis superior to wall thickening analysis in discriminating infarct from remote myocardium.

OBJECTIVES: Using two-dimensional wall thickening (WT) (expressed as percentage) and strain analysis, regional contractile myocardial function was quantified and compared in 13 control subjects and 13 patients with a first myocardial infarction (MI). The findings in the patient group were related to global ventricular function and infarct size. BACKGROUND: In patients with coronary artery disease, regions with dysfunctional myocardium cannot be differentiated easily from regions with normal function by planar WT analysis. Physiologic factors, in combination with limitations of conventional imaging techniques, affect the calculation of WT. Quantitative assessment of contractile function by magnetic resonance (MR) tissue tagging and strain analysis may be less affected by these factors. METHODS: Two-dimensional regional WT and strain were calculated in three short-axis MR cine and tagged images, respectively. Left ventricular volumes and ejection fraction (EF) were obtained from a series of contiguous short-axis cine images. RESULTS: In patients with infarct-related ventricles, WT and strain analysis both revealed reduced myocardial function, as compared with control subjects (p < 0.005 and p < 0.001, respectively). However, WT analysis yielded no significant regional differences in function between infarct-related and remote myocardium (p = 0.064), whereas strain analysis did (p < 0.005). For detecting dysfunctional myocardium of electrocardiographically and angiographically defined infarct areas, WT analysis had a sensitivity of 69% and a specificity of 92%, whereas strain analysis demonstrated a sensitivity of 92% and a specificity of 99%. The EF correlated with WT (r = 0.76, p < 0.005) and strain (r = 0.89, p < 0.001). CONCLUSIONS: Two-dimensional strain analysis is more accurate than planar WT analysis in discriminating dysfunctional from functional myocardium, and it provides a strong correlation between regional myocardial and global ventricular function.

Improved harmonic phase myocardial strain maps.

Magnetic resonance tagging has proven a valuable tool in the quantification of myocardial deformation. However, time-consuming postprocessing has discouraged the use of this technique in clinical routine. Recently, the harmonic phase (HARP) technique was introduced for automatic calculation of myocardial strain maps from tagged images. In this study, a comparison was made between HARP instantaneous strain maps calculated from single tagged images (SPAMM) and those calculated from subtracted tagged images (CSPAMM). The performance was quantified using simulated images of an incompressible cylinder in the 'end-systolic' state with realistic image contrast and noise. The error in the second principal stretch ratio was 0.009 +/- 0.032 (mean +/- SD) for the SPAMM acquisition, and 0.007 +/- 0.016 for CSPAMM at identical contrast-to-noise ratio. Furthermore, differences between the methods were illustrated with in vivo strain maps. Those calculated from CSPAMM images showed fewer artifacts and were less sensitive to the choice of cut-off frequencies in the HARP band-pass filter. A prerequisite for the method to become practical is that the CSPAMM images should be acquired in a single breathhold.

Variance components of two-dimensional strain parameters in the left-ventricular heart wall obtained by magnetic resonance tagging.

This study quantifies variance components of two-dimensional strains in the left-ventricular heart wall assessed by magnetic resonance (MR) tagging in 18 healthy xxvolunteers. For a 7-mm tagging grid and homogeneous strain analysis, the intersubject variability and measurement error were estimated, as well as the intra- and interobserver variability. The variance components were calculated for the mean strain of a circumferential sector. The results show that the measurement error was almost equal to the intra-observer variability. With four circumferential sectors of 90 degrees each, approximately 65% of the total variance in epsilonr and epsilonc was due to intersubject variability, the remaining 35% was due to measurement error. With 12 sectors of 30 degrees each, the intersubject variability and measurement error both contributed 50% to the total variance. With 18 sectors of 20 degrees each, only 40% of the total variance was due to intersubject variability. The total variability increased with the number of sectors and therefore the number of sectors used in a study will be a trade-off between segment size (defining spatial resolution) and variability.

Impaired left ventricular filling due to right ventricular pressure overload in primary pulmonary hypertension: noninvasive monitoring using MRI.

OBJECTIVE: To analyze the effect of primary pulmonary hypertension (PPH) on cardiac function using MRI. METHODS: In 12 patients (9 women; age range, 30 to 56 years), the diagnosis of PPH had been established by catheterization (mean +/- SD pulmonary artery pressure [PAP] was 56 +/- 8 mm Hg). With breath-hold cine MRI, a series of short-axis images was acquired covering the whole left ventricle (LV) and right ventricle (RV). The curvature, defined as 1 divided by the radius of curvature in centimeters, was calculated for the septum and the LV free wall in early diastole. Leftward ventricular septal bowing (LVSB) is denoted by a negative curvature. For the LV and the RV, the end-diastolic volume (EDV), stroke volume (SV), and volumetric filling rate were calculated. The control subjects were all healthy (n = 14; 11 women; age range, 20 to 57 years). RESULTS: In the patients, LVSB was quantified in early diastole by the septal curvature of - 0.14 +/- 0.07 cm(-1), and the septal to free-wall curvature ratio of - 0.42 +/- 0.21. LV EDV and LV SV correlated negatively with diastolic PAP (p = 0.004 and p = 0.04, respectively). In patients vs control subjects, RV SV was reduced (52 +/- 12 mL vs 82 +/- 11 mL, p < 0.0001); LV peak filling rate was smaller (2.2 +/- 0.7 EDV/s vs 3.3 +/- 0.5 EDV/s, p < 0.001); LV EDV was smaller (81 +/- 23 mL vs 117 +/- 19 mL, p = 0.001); and LV SV was smaller (49 +/- 18 mL vs 83 +/- 13 mL, p < 0.0001). CONCLUSION: In PPH, RV pressure overload leads to LVSB and reduced RV output. By decreased blood delivery, LV filling is reduced, which results in decreased LV SV by the Frank-Starling mechanism.