In vivo quantification of myocardial stiffness in hypertensive porcine hearts using MR elastography.

PURPOSE: To determine alteration in left ventricular (LV) myocardial stiffness (MS) with hypertension (HTN). Cardiac MR elastography (MRE) was used to estimate MS in HTN induced pigs and MRE-derived MS measurements were compared against LV pressure, thickness and circumferential strain. MATERIALS AND METHODS: Renal-wrapping surgery was performed to induce HTN in eight pigs. LV catheterization (to measure pressure) and cardiac MRI (1.5 Tesla; gradient echo-MRE and tagging) was performed pre-surgery at baseline (Bx), and post-surgery at month 1 (M1) and month 2 (M2). Images were analyzed to estimate LV-MS, thickness, and circumferential strain across the cardiac cycle. The associations between end-diastolic (ED) and end-systolic (ES) MS and (i) mean LV pressure; (ii) ED and ES thickness, respectively; and (iii) circumferential strain were evaluated using Spearman's correlation method. RESULTS: From Bx to M2, mean pressure, MRE-derived stiffness, and thickness increased while circumferential strain decreased significantly (slope test, P ≤ 0.05). Both ED and ES MS had significant positive correlation with (i) mean pressure (ED MS: ρ = 0.56; P = 0.005 and ES MS: ρ = 0.45; P = 0.03); (ii) ED thickness ( ρ = 0.73; P < 0.0001) and ES thickness ( ρ = 0.84; P < 0.0001), respectively; but demonstrated a negative trend with circumferential strain (ED MS: ρ = 0.31 and ES MS: ρ = 0.37). CONCLUSION: This study demonstrated that, in a HTN porcine model, MRE-derived MS increased with increase in pressure and thickness. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:813-820.

In vivo magnetic resonance elastography to estimate left ventricular stiffness in a myocardial infarction induced porcine model.

PURPOSE: To estimate change in left ventricular (LV) end-systolic and end-diastolic myocardial stiffness (MS) in pigs induced with myocardial infarction (MI) with disease progression using cardiac magnetic resonance elastography (MRE) and to compare it against ex vivo mechanical testing, LV circumferential strain, and magnetic resonance imaging (MRI) relaxometry parameters (T1 , T2 , and extracellular volume fraction [ECV]). MATERIALS AND METHODS: MRI (1.5T) was performed on seven pigs, before surgery (Bx), and 10 (D10), and 21 (D21) days after creating MI. Cardiac MRE-derived MS was measured in infarcted region (MIR) and remote region (RR), and validated against mechanical testing-derived MS obtained postsacrifice on D21. Circumferential strain and MRI relaxometry parameters (T2 , T1 , and ECV) were also obtained. Multiparametric analysis was performed to determine correlation between cardiac MRE-derived MS and 1) strain, 2) relaxometry parameters, and 3) mechanical testing. RESULTS: Mean diastolic (D10: 5.09 ± 0.6 kPa; D21: 5.45 ± 0.7 kPa) and systolic (D10: 5.72 ± 0.8 kPa; D21: 6.34 ± 1.0 kPa) MS in MIR were significantly higher (P < 0.01) compared to mean diastolic (D10: 3.97 ± 0.4 kPa; D21: 4.12 ± 0.2 kPa) and systolic (D10: 5.08 ± 0.6 kPa; and D21: 5.16 ± 0.6 kPa) MS in RR. The increase in cardiac MRE-derived MS at D21 (MIR) was consistent and correlated strongly with mechanical testing-derived MS (r(diastolic) = 0.86; r(systolic) = 0.89). Diastolic MS in MIR demonstrated a negative correlation with strain (r = 0.58). Additionally, cardiac MRE-derived MS demonstrated good correlations with post-contrast T1 (r(diastolic) = -0.549; r(systolic) = -0.741) and ECV (r(diastolic) = 0.548; r(systolic) = 0.703), and no correlation with T2 . CONCLUSION: As MI progressed, cardiac MRE-derived MS increased in MIR compared to RR, which significantly correlated with mechanical testing-derived MS, T1 and ECV. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1024-1033.

Electrotonic remodeling following myocardial infarction in dogs susceptible and resistant to sudden cardiac death.

Passive electrical remodeling following myocardial infarction (MI) is well established. These changes can alter electrotonic loading and trigger the remodeling of repolarization currents, a potential mechanism for ventricular fibrillation (VF). However, little is known about the role of passive electrical markers as tools to identify VF susceptibility post-MI. This study investigated electrotonic remodeling in the post-MI ventricle, as measured by myocardial electrical impedance (MEI), in animals prone to and resistant to VF. MI was induced in dogs by a two-stage left anterior descending (LAD) coronary artery ligation. Before infarction, MEI electrodes were placed in remote (left circumflex, LCX) and infarcted (LAD) myocardium. MEI was measured in awake animals 1, 2, 7, and 21 days post-MI. Subsequently, VF susceptibility was tested by a 2-min LCX occlusion during exercise; 12 animals developed VF (susceptible, S) and 12 did not (resistant, R). The healing infarct had lower MEI than the normal myocardium. This difference was stable by day 2 post-MI (287 +/- 32 Omega vs. 425 +/- 62 Omega, P < 0.05). Significant differences were observed between resistant and susceptible animals 7 days post-MI; susceptible dogs had a wider electrotonic gradient between remote and infarcted myocardium (R: 89 +/- 60 Omega vs. S: 180 +/- 37 Omega). This difference increased over time in susceptible animals (252 +/- 53 Omega at 21 days) due to post-MI impedance changes on the remote myocardium. These data suggest that early electrotonic changes post-MI could be used to assess later arrhythmia susceptibility. In addition, passive-electrical changes could be a mechanism driving active-electrical remodeling post-MI, thereby facilitating the induction of arrhythmias.

Adaptive anisotropic gaussian filtering to reduce acquisition time in cardiac diffusion tensor imaging.

Diffusion tensor imaging (DTI) is used to quantify myocardial fiber orientation based on helical angles (HA). Accurate HA measurements require multiple excitations (NEX) and/or several diffusion encoding directions (DED). However, increasing NEX and/or DED increases acquisition time (TA). Therefore, in this study, we propose to reduce TA by implementing a 3D adaptive anisotropic Gaussian filter (AAGF) on the DTI data acquired from ex-vivo healthy and infarcted porcine hearts. DTI was performed on ex-vivo hearts [9-healthy, 3-myocardial infarction (MI)] with several combinations of DED and NEX. AAGF, mean (AVF) and median filters (MF) were applied on the primary eigenvectors of the diffusion tensor prior to HA estimation. The performance of AAGF was compared against AVF and MF. Root mean square error (RMSE), concordance correlation-coefficients and Bland-Altman's technique was used to determine optimal combination of DED and NEX that generated the best HA maps in the least possible TA. Lastly, the effect of implementing AAGF on the infarcted porcine hearts was also investigated. RMSE in HA estimation for AAGF was lower compared to AVF or MF. Post-filtering (AAGF) fewer DED and NEX were required to achieve HA maps with similar integrity as those obtained from higher NEX and/or DED. Pathological alterations caused in HA orientation in the MI model were preserved post-filtering (AAGF). Our results demonstrate that AAGF reduces TA without affecting the integrity of the myocardial microstructure.

Diffusion Tensor Imaging of Healthy and Infarcted Porcine Hearts: Study on the Impact of Formalin Fixation.

BACKGROUND: Due to complexities of in-vivo cardiac diffusion tensor imaging (DTI), ex-vivo formalin-fixed specimens are used to investigate cardiac remodeling in diseases, and reported results have shown conflicting trends. This study investigates the impact of formalin-fixation on diffusion properties and optimizes tracking parameters based on controls to understand remodeling in myocardial-infarction (MI). METHODS: DTI was performed on 4 healthy (controls) and 4 MI induced formalin-fixed (PoMI) ex-vivo porcine hearts. Controls were scanned pre-fixation (PrCtrl) and re-scanned (PoCtrl) after formalin-fixation. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were estimated in all hearts. Tracking parameters (FA, tract termination angle (TTA), fiber-length) were optimized in controls and then used to investigate structural remodeling in PoMI hearts. RESULTS: Fixation increased ADC and decreased FA. PoMI showed increased ADC but decreased FA in infarcted zone compared to remote zone. TTA showed sharp increase in slope from 5°-10°, which flattened after 25° in all groups. Mean fiber-length for different tracking length range showed that PoCtrl had shorter fibers compared to PrCtrl. Fibers around infarction were shorter in length and disarrayed compared to PoCtrl group. CONCLUSION: Formalin-fixation affects diffusion properties and hence DTI parametric trends observed in pathology may be influenced by the fixation process which can cause contradictory findings.

Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans.

Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs. Here, interspecies differences in three MEI parameters (baseline, time to plateau onset, and plateau value normalized by baseline) were evaluated using Kruskal-Wallis ANOVA and post hoc tests (P < 0.05). Noteworthy differences in the MEI time to plateau onset were observed: In dogs, MEI ischemic plateau was reached after 46.3 min (SD 12.9) min of occlusion, a significantly longer period compared with that of pigs and humans [4.7 (SD 1.2) and 4.1 min (SD 1.9), respectively]. However, no differences could be observed between both animal species regarding the normalized MEI ischemic plateau value (15.3% (SD 4.7) in pigs, vs. 19.6% (SD 2.6) in dogs). For all studied MEI parameters, only swine values resembled those of humans. The severity of myocardial supply ischemia, resulting from coronary artery occlusion, is known to be dependent on collateral flow. Thus, because dogs possess a well-developed collateral system (unlike humans or pigs), they have shown superior resistance to occlusion of a coronary artery. Here, the early MEI time course after left anterior descending coronary artery occlusion, represented by the time required to reach ischemic plateau, was proven to reflect such interspecies differences.

Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for ß-adrenoceptor mediated enhanced coupling during exercise testing.

INTRODUCTION: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF). METHODS: Dogs (n = 25) with healed MI instrumented for MEI measurements were trained to run on a treadmill and classified based on their susceptibility to VF (12 susceptible, 9 resistant). MEI and ECGs were recorded during 6-stage exercise tests (18 min/test; peak: 6.4 km/h @ 16%) performed under control conditions, and following complete ß-adrenoceptor (ß-AR) blockade (propranolol); MEI was also measured at rest during escalating ß-AR stimulation (isoproterenol) or overdrive-pacing. RESULTS: Exercise progressively increased heart rate (HR) and reduced heart rate variability (HRV). In parallel, MEI decreased gradually (enhanced electrotonic coupling) with exercise; at peak exercise, MEI was reduced by 5.3 ± 0.4% (or -23 ± 1.8Ω, P < 0.001). Notably, exercise-mediated electrotonic changes were linearly predicted by the degree of autonomic activation, as indicated by changes in either HR or in HRV (P < 0.001). Indeed, ß-AR blockade attenuated the MEI response to exercise while direct ß-AR stimulation (at rest) triggered MEI decreases comparable to those observed during exercise; ventricular pacing had no significant effects on MEI. Finally, animals prone to VF had a significantly larger MEI response to exercise. CONCLUSIONS: These data suggest that ß-AR activation during exercise can acutely enhance electrotonic coupling in the myocardium, particularly in dogs susceptible to ischemia-induced VF.

Three-dimensional numerical simulations of susceptibility-induced magnetic field inhomogeneities in the human head.

Three-dimensional numerical simulations of the static magnetic field in the human head were carried out to assess the field inhomogeneity due to magnetic susceptibility differences at tissue interfaces. We used a finite difference method and magnetic permeability distributions obtained by segmentation of computed tomography images. Computations were carried out for four models, consisting of the head and the neck; the head, neck, and shoulders; the head, neck, and thorax; and the head tilted backwards, including the neck and the shoulders. Considerable magnetic field inhomogeneities were observed in the inferior frontal lobes and inferior temporal lobes, particularly near the sphenoid sinus and the temporal bones. Air/tissue interfaces at the shoulders were found to induce substantial magnetic field inhomogeneities in the occipital lobes and the cerebellum, whereas air/tissue interfaces in the lungs appeared to have less influence on the magnetic field in the brain. Tilting the head backwards could significantly reduce the field inhomogeneities superior to the planum sphenoidale as well as in the occipital lobes and the cerebellum.

Comparison of super resolution reconstruction acquisition geometries for use in mouse phenotyping.

3D isotropic imaging at high spatial resolution (30-100 microns) is important for comparing mouse phenotypes. 3D imaging at high spatial resolutions is limited by long acquisition times and is not possible in many in vivo settings. Super resolution reconstruction (SRR) is a postprocessing technique that has been proposed to improve spatial resolution in the slice-select direction using multiple 2D multislice acquisitions. Any 2D multislice acquisition can be used for SRR. In this study, the effects of using three different low-resolution acquisition geometries (orthogonal, rotational, and shifted) on SRR images were evaluated and compared to a known standard. Iterative back projection was used for the reconstruction of all three acquisition geometries. The results of the study indicate that super resolution reconstructed images based on orthogonally acquired low-resolution images resulted in reconstructed images with higher SNR and CNR in less acquisition time than those based on rotational and shifted acquisition geometries. However, interpolation artifacts were observed in SRR images based on orthogonal acquisition geometry, particularly when the slice thickness was greater than six times the inplane voxel size. Reconstructions based on rotational geometry appeared smoother than those based on orthogonal geometry, but they required two times longer to acquire than the orthogonal LR images.

Improved in vivo human carotid artery wall T2 estimation.

T(2) quantification has been shown to noninvasively and accurately estimate tissue iron content in the liver and heart; applying this to thin-walled carotid arteries introduces a new challenge to the estimation process. With most imaging voxels in a vessel being along its boundaries, errors in parameter estimation may result from partial volume mixing and misregistration due to motion in addition to noise and other common error sources. To minimize these errors, we propose a novel technique to reliably estimate T(2) in thin regions of vessel wall. The technique weights data points to reduce the influence of expected error sources. It uses neighborhoods of data to increase the number of points for fitting and to assess lack of fit for automated outlier detection and deletion. The performance of this method was observed in simulations, phantom and in vivo patient studies and compared to results obtained using a pixelwise linear least squares estimation of T(2). The new proposed method showed a closer match to the expected results, and a 4.2-fold decrease in interobserver variability for in vivo studies. This increased confidence in estimation should improve the ability to reliably quantify iron noninvasively in the arterial wall.

Unexpectedly high prevalence of sarcoidosis in a representative U.S. Metropolitan population.

The prevalence of sarcoidosis in the United States is unknown, with estimates ranging widely from 1 to 40 per 100,000. We sought to determine the prevalence of sarcoidosis in our health system compared to other rare lung diseases and to further establish if the prevalence was changing over time. We interrogated the electronic medical records of all patients treated in our health system from 1995 to 2010 (1.48 million patients) using the common ICD9 codes for sarcoidosis (135), lung cancer (162), and several other lung diseases characterized, like sarcoidosis, as "rare lung diseases". The patient demographic information (race, gender, age) was further analyzed to identify signature data patterns. The prevalence of sarcoidosis in our health system increased steadily from 164/100,000 in 1995 to 330/100,000 in 2010, and this trend could not be ascribed simply to changes in patient demographics or patient referral patterns. We further estimate that the prevalence of sarcoidosis exceeds 48 per 100,000 in Franklin County, Ohio, the demographic profile of which is nearly identical to that of the U.S. Sarcoidosis prevalence increased over time relative to lung cancer, a benchmark disease with stable disease prevalence, and exceeded that of other rare lung diseases. We postulate that the observed 2-fold increase in sarcoidosis disease prevalence in our health system is primarily related to improved detection and diagnostic approaches, and we conclude that the actual prevalence of sarcoidosis in central Ohio greatly exceeds current U.S. estimates.

Quantitative computerized two-point correlation analysis of lung CT scans correlates with pulmonary function in pulmonary sarcoidosis.

BACKGROUND: Chest CT scans are commonly used to clinically assess disease severity in patients presenting with pulmonary sarcoidosis. Despite their ability to reliably detect subtle changes in lung disease, the utility of chest CT scans for guiding therapy is limited by the fact that image interpretation by radiologists is qualitative and highly variable. We sought to create a computerized CT image analysis tool that would provide quantitative and clinically relevant information. METHODS: We established that a two-point correlation analysis approach reduced the background signal attendant to normal lung structures, such as blood vessels, airways, and lymphatics while highlighting diseased tissue. This approach was applied to multiple lung fields to generate an overall lung texture score (LTS) representing the quantity of diseased lung parenchyma. Using deidentified lung CT scan and pulmonary function test (PFT) data from The Ohio State University Medical Center's Information Warehouse, we analyzed 71 consecutive CT scans from patients with sarcoidosis for whom simultaneous matching PFTs were available to determine whether the LTS correlated with standard PFT results. RESULTS: We found a high correlation between LTS and FVC, total lung capacity, and diffusing capacity of the lung for carbon monoxide (P < .0001 for all comparisons). Moreover, LTS was equivalent to PFTs for the detection of active lung disease. The image analysis protocol was conducted quickly (< 1 min per study) on a standard laptop computer connected to a publicly available National Institutes of Health ImageJ toolkit. CONCLUSIONS: The two-point image analysis tool is highly practical and appears to reliably assess lung disease severity. We predict that this tool will be useful for clinical and research applications.

Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation.

Parasympathetic activity during acute coronary artery occlusion (CAO) can protect against ischaemia-induced malignant arrhythmias; nonetheless, the mechanism mediating this protection remains unclear. During CAO, myocardial electrotonic uncoupling is associated with autonomically mediated immediate (i.e. type 1A) arrhythmias and can modulate pro-arrhythmic dispersion of repolarization. Therefore, the effects of acutely enhanced or decreased cardiac parasympathetic activity on early electrotonic coupling during CAO, as measured by myocardial electrical impedance (MEI), were investigated. Anaesthetized dogs were instrumented for MEI measurements, and left circumflex coronary arterial occlusions were performed in intact (CTRL) and vagotomized (VAG) animals. The CAO was followed by either vagotomy (CTRL) or vagal nerve stimulation (VNS, 10 Hz, 10 V) in the VAG dogs. Vagal nerve stimulation was studied in two additional sets of animals. In one set heart rate (HR) was maintained by pacing (220 beats min(-1)), while in the other set bilateral stellectomy preceded CAO. The MEI increased after CAO in all animals. A larger MEI increase was observed in vagotomized animals (+85 +/- 9 Omega, from 611 +/- 24 Omega, n = 16) when compared with intact control dogs (+43 +/- 5 Omega, from 620 +/- 20 Omega, n = 7). Acute vagotomy during ischaemia abruptly increased HR (from 155 +/- 11 to 193 +/- 15 beats min(-1)) and MEI (+12 +/- 1.1 Omega, from 663 +/- 18 Omega). In contrast, VNS during ischaemia (n = 11) abruptly reduced HR (from 206 +/- 6 to 73 +/- 9 beats min(-1)) and MEI (-16 +/- 2 Omega, from 700 +/- 44 Omega). These effects of VNS were eliminated by pacing but not by bilateral stellectomy. Vagal nerve stimulation during CAO also attenuated ECG-derived indices of ischaemia (e.g. ST segment, 0.22 +/- 0.03 versus 0.15 +/- 0.03 mV) and of rate-corrected repolarization dispersion [terminal portion of T wave (TPEc), 84.5 +/- 4.2 versus 65.8 +/- 5.9 ms; QTc, 340 +/- 8 versus 254 +/- 16 ms]. Vagal nerve stimulation during myocardial ischaemia exerts negative chronotropic effects, limiting early ischaemic electrotonic uncoupling and dispersion of repolarization, possibly via a decreased myocardial metabolic demand.

Multispectral co-occurrence with three random variables in dynamic contrast enhanced magnetic resonance imaging of breast cancer.

Presented is a new computer-aided multispectral image processing method which is used in three spatial dimensions and one spectral dimension where the dynamic, contrast enhanced magnetic resonance parameter maps derived from voxel-wise model-fitting represent the spectral dimension. The method is based on co-occurrence analysis using a 3-D window of observation which introduces an automated identification of suspicious lesions. The co-occurrence analysis defines 21 different statistical features, a subset of which were input to a neural network classifier where the assessments of the voxel-wise majority of a group of radiologist readings were used as the gold standard. The voxel-wise true positive fraction (TPF) and false positive fraction (FPF) results of the computer classifier were statistically indistinguishable from the TPF and FPF results of the readers using a one sample paired t-test. In order to observe the generality of the method, two different groups of studies were used with widely different image acquisition specifications.

Malignant-lesion segmentation using 4D co-occurrence texture analysis applied to dynamic contrast-enhanced magnetic resonance breast image data.

PURPOSE: To investigate the use of four-dimensional (4D) co-occurrence-based texture analysis to distinguish between nonmalignant and malignant tissues in dynamic contrast-enhanced (DCE) MR images. MATERIALS AND METHODS: 4D texture analysis was performed on DCE-MRI data sets of breast lesions. A model-free neural network-based classification system assigned each voxel a "nonmalignant" or "malignant" label based on the textural features. The classification results were compared via receiver operating characteristic (ROC) curve analysis with the manual lesion segmentation produced by two radiologists (observers 1 and 2). RESULTS: The mean sensitivity and specificity of the classifier agreed with the mean observer 2 performance when compared with segmentations by observer 1 for a 95% confidence interval, using a two-sided t-test with alpha = 0.05. The results show that an area under the ROC curve (A(z)) of 0.99948, 0.99867, and 0.99957 can be achieved by comparing the classifier vs. observer 1, classifier vs. union of both observers, and classifier vs. intersection of both observers, respectively. CONCLUSION: This study shows that a neural network classifier based on 4D texture analysis inputs can achieve a performance comparable to that achieved by human observers, and that further research in this area is warranted.

Three-dimensional texture analysis of cancellous bone cores evaluated at clinical CT resolutions.

The objective of this study was to determine if three-dimensional (3D) Haralick co-occurrence texture measures calculated from low-resolution CT images of trabecular bone correlate with 3D structural indices measured from high-resolution CT images. Thirty-three cubical regions of trabecular bone from human calcanei were analyzed using images obtained from a micro-computed tomography (micro-CT) scanner. 3D measures of bone architecture were calculated. The original images were then subsampled by factors of 5, 10, 15, and 20, and 3D texture features were calculated for each set of subsampled images. Linear regression models showed that co-occurrence texture features were significantly correlated with structural indices. Over 90% of the variation in three different structural indices was explained in two-variable regression models using texture features as predictors when the voxel side length was reduced by a factor of 10. Texture features calculated from clinical images may increase our ability to obtain trabecular bone architectural information when high-resolution images are unobtainable.