Nilesh R Ghugre

Practical medical applications of quantitative MR relaxometry.

Conventional MR images are qualitative, and their signal intensity is dependent on several complementary contrast mechanisms that are manipulated by the MR hardware and software. In the absence of a quantitative metric for absolute interpretation of pixel signal intensities, one that is independent of scanner hardware and sequences, it is difficult to perform comparisons of MR images across subjects or longitudinally in the same subject. Quantitative relaxometry isolates the contributions of individual MR contrast mechanisms (T1, T2, T2*) and provides maps, which are independent of the MR protocol and have a physical interpretation often expressed in absolute units. In addition to providing an unbiased metric for comparing MR scans, quantitative relaxometry uses the relationship between MR maps and physiology to provide a noninvasive surrogate for biopsy and histology. This study provides an overview of some promising clinical applications of quantitative relaxometry, followed by a description of the methods and challenges of acquiring accurate and precise quantitative MR maps. It concludes with three case studies of quantitative relaxometry applied to studying multiple sclerosis, liver iron, and acute myocardial infarction. J. Magn. Reson. Imaging 2012;36:805–824.

Intrinsic Contrast for Characterization of Acute Radiofrequency Ablation Lesions

Background—Both intrinsic contrast (T1 and T2 relaxation and the equilibrium magnetization) and contrast agent (gadolinium)–enhanced MRI are used to visualize and evaluate acute radiofrequency ablation lesions. However, current methods are imprecise in delineating lesion extent shortly after the ablation. Methods and Results—Fifteen lesions were created in the endocardium of 13 pigs. A multicontrast inversion recovery steady state free precession imaging method was used to delineate the acute ablation lesions, exploiting T1-weighted contrast. T2 and Mo* maps were also created from fast spin echo data in a subset of pigs (n=5) to help characterize the change in intrinsic contrast in the lesions. Gross pathology was used as reference for the lesion size comparison, and the lesion structures were confirmed with histological data. In addition, a colorimetric iron assay was used to measure ferric and ferrous iron content in the lesions and the healthy myocardium in a subset of pigs (n=2). The lesion sizes measured in inversion recovery steady state free precession images were highly correlated with the extent of lesion core identified in gross pathology. Magnetic resonance relaxometry showed that the radiofrequency ablation procedure changes the intrinsic T1 value in the lesion core and the intrinsic T2 in the edematous region. Furthermore, the T1 shortening appeared to be correlated with the presence of ferric iron, which may have been associated with metmyoglobin and methemoglobin in the lesions. Conclusions—The study suggests that T1 contrast may be able to separate necrotic cores from the surrounding edematous rims in acute radiofrequency ablation lesions.

High-Resolution 3-D T

The substrate of potentially lethal cardiac arrhythmias often resides in the gray zone (GZ), a mixture of viable myocytes and collagen strands found between healthy myocardium and infarct core (IC). The specific aims of this paper are to demonstrate correspondence between regions delineated in T1* (apparent T1) maps and tissue characteristics seen in histopathology and to determine the MR imaging resolution needed to adequately identify GZ-associated substrate in chronic infarct. For this, a novel 3-D multicontrast late enhancement (MCLE) MR method was used to image ex vivo swine hearts with chronic infarction, at high resolution (0.6 × 0.6 × 1.25 mm). Pixel-wise classified tissue maps were calculated using steady-state and T1 * images as input to a fuzzy-clustering algorithm. Quantitative histology based on collagen stains was performed in n = 10 selected slabs and showed very good correlations between histologically-determined areas of heterogeneous and dense fibrosis, and the corresponding GZ (R2 = 0.96) and IC (R2 = 0.97) in tissue classified maps. Furthermore, in n = 24 slabs, we performed volumetric measurements of GZ and IC, at the original and decreased image resolutions. Our results demonstrated that the IC volume remained relatively unchanged across all resolutions, whereas the GZ volume progressively increased with diminished image resolution, with changes reaching significance at 1 × 1 × 5 mm resolution (p <; 0.05) but not at 1 × 1 × 2.5 mm, suggesting that this resolution may be sufficient to adequately identify the GZ from MCLE images, enabling an effective MR probing of remodeled myocardium in late infarct. Future work will focus on translating these findings to optimizing the current in vivo MCLE imaging of the GZ.

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&NA; Cell autonomous circadian “clock” mechanisms are present in virtually every organ, and generate daily rhythms that are important for normal physiology. This is especially relevant to the cardiovascular system, for example the circadian mechanism orchestrates rhythms in heart rate, blood pressure, cardiac contractility, metabolism, gene and protein abundance over the 24‐h day and night cycles. Conversely, disturbing circadian rhythms (e.g. via shift work, sleep disorders) increases cardiovascular disease risk, and exacerbates cardiac remodelling and worsens outcome. Notably, reactive oxygen species (ROS) are important contributors to heart disease, especially the pathophysiologic damage that occurs after myocardial infarction (MI, heart attack). However, little is known about how the circadian mechanism, or rhythm desynchrony, is involved in these key pathologic stress responses. This review summarizes the current knowledge on circadian rhythms in the cardiovascular system, and the implications of rhythm disturbances for cardiovascular health. Furthermore, we highlight how free radical biology coincides with the pathogenesis of myocardial repair and remodelling after MI, and indicate a role for the circadian system in the oxidative stress pathways in the heart and brain after MI. This fusion of circadian biology with cardiac oxidative stress pathways is novel, and offers enormous potential for improving our understanding and treatment of heart disease.

-Mapping and Quantitative Image Analysis of GRAY ZONE in Chronic Fibrosis

Methods 15 lesions were created in the endocardium of 13 pigs using approved animal protocols. NGE IR-SSFP and T2-w black-blood (double IR-FSE) images were acquired in <60min after ablation. Then, Gd-DTPA (Magnevist, 0.2 mmol/kg) was injected and LGE images were acquired repeatedly over one hour. Gross pathology was used as the reference for lesion size measurements. Two regions were measured in this reference: the pale “inner” lesion core and the “outer” lesion border including the dark rim on pathology (see Results).

Implications of disturbances in circadian rhythms for cardiovascular health: A new frontier in free radical biology

Background Cardiac MR has been used successfully in RF ablation therapies for arrhythmias, both for procedural planning and for post-ablation lesion imaging. Non-enhanced imaging, though it has a lower SNR, has advantages over Gdenhanced techniques mainly because contrast kinetics and dosage issues are avoided. Previously T2-weighted imaging was found to be more sensitive than T1-weighted imaging [1]. In this study, we performed non-enhanced T2 mapping and an inversion-prepared SSFP CINE imaging to characterize intrinsic relaxation behavior in acute lesions.

Evaluating the extent of acute radiofrequency ablation lesions in the heart using an inversion recovery SSFP sequence

Summary Reperfusion hemorrhage is an independent predictor of adverse left-ventricular remodeling following acute myocardial infarction. Iron chelation may potentially alleviate the toxic and pro-inflammatory effects of iron degradation products. CMR can provide insights into the interaction between hemorrhage and iron chelator. Background It has been speculated that iron chelation may be beneficial in acute myocardial infarction (AMI) and that early treatment can limit ischemia-reperfusion injury and also reduce infarct size. However, the role of iron chelation in hemorrhagic myocardial infarction, where it would be most suited, has not yet been explored. Reperfusion hemorrhage results in accumulation of iron degradation products of hemoglobin that may be proinflammatory as free iron is toxic in nature. The purpose of the study was to investigate the interaction between iron chelating agent deferiprone (DFP) and hemorrhage in a porcine model of myocardial infarction and monitor remodeling by cardiovascular magnetic resonance (CMR). Methods The study involved two groups of animals that were subjected to a 90 min balloon occlusion of the LAD followed by reperfusion - untreated (N=2) and DFP treated (N=2). DFP (supported by ApoPharma Inc., Toronto, ON) was administered (orally) a few hours before the procedure (pre-loading) and treatment was continued with a daily dose of 100 mg/kg. Imaging was performed on a 3T MRI scanner (MR 750, GE Healthcare) preAMI (healthy) and day 2-week 4 post-AMI. Edema was evaluated by T2 quantification using a T2-prepared spiral sequence and hemorrhage was identified by T2* determined using a multi-echo gradient-echo acquisition. Infarct assessment was performed by delayed hyperenhancement (DHE) using an IR-GRE sequence. Results Figure 1 demonstrates representative images from the two groups while Figure 2 shows the cumulative time course of the CMR measurements. In the DFP group, hemorrhage was observed only on day 2 and by week 1 it had completely resolved. This was in contrast to the untreated group where resolution of hemorrhage was delayed to week 4. With DFP, inflammation or edema was substantially reduced by week 4 with T2 values approaching control levels. In the untreated group, edema persisted up to week 4. Ejection fraction (EF) was depressed by week 4 in both groups. However, enddiastolic and end-systolic volumes were relatively unchanged in the DFP group while they increased significantly in the untreated group. Conclusions

Exploring intrinsic MR signal relaxation in acute RF ablation lesions using T2 mapping and IR-SSFP CINE imaging

Background Reperfusion no-reflow (R-NR), characterized by TIMI 0/1 flow grade, is a phenomenon that occurs in up to 20% of percutaneous coronary intervention cases for acute myocardial infarction (AMI). R-NR involves reduced myocardial tissue perfusion in the presence of a reperfused and patent epicardial coronary artery. This phenomenon is associated with worse patient outcome and increased mortality. Potential contributing factors of R-NR include the initial ischemic insult, injury as a result of reperfusion, and possibly distal coronary embolization (DCE) of thrombotic material. The objective of this study was to develop a novel large animal model to investigate the effects of DCE in the setting of ischemia-reperfusion using microthrombi derived from autologous porcine blood. Methods 3.0 T CMR was performed on 25-30kg female Yorkshire pigs to determine baseline values of cardiac function, as well as the myocardial perfusion territory at risk using direct intracoronary injection of dilute GadoliniumDTPA. Pigs were then subjected to balloon occlusion mediated myocardial ischemia distal to the second diagonal branch of the left anterior descending coronary artery (LAD) for 60 minutes. Following reperfusion, intracoronary injection of sterile saline (n=4) or microthrombi particles to simulate DCE (n=7) was performed. Epicardial coronary blood flow was assessed at each stage using x-ray angiography. At 72 hours following ischemia-reperfusion, CMR was used to assess changes in cardiac function, extent of edema/hemorrhage using T2/T2* relaxation times, evaluate infarct size, and to determine the presence/absence of microvascular obstruction (MVO). Myocardial tissue samples were subsequently collected for biochemical and histological analysis.

Role of iron chelation in hemorrhagic myocardial infarction: a quantitative CMR study

The purpose of this work was to use in vivo MR imaging and electro-anatomical maps to characterize dense scars and border zone, BZ (a mixture of collagen and viable fibers). To better understand how these measures might probe potentially arrhythmogenic substrates, we developed a preclinical swine model of chronic infarction and integrated in vivo MRI and electrophysiology (EP) data in five swine at 5-6 weeks post-infarction. Specifically, we first aligned and registered T1-maps (from MR studies) and bipolar voltage maps (from CARTO-EP studies) using Vurtigo, an open source software. We then performed a quantitative analysis based on circumferential segments defined in the short-axis of MR images. Our results demonstrated a negative linear relation between bipolar voltage maps and T1 maps within the first two mm of the endocardial surface. The results of our novel approach suggest that T1-maps combined with limited EP measurements can be used to evaluate the biophysical properties of healing myocardium post-infarction, and to distinguish between the infarct categories (i.e., dense scar vs. BZ) with remodelled electrical characteristics.

The effect of distal coronary embolization on infarct size in a porcine acute myocardial infarction model

Summary The clinical implications of hemorrhagic versus nonhemorrhagic infarcts are currently unclear. Our study suggests that hemorrhage may not simply be a bystander but an active contributor to adverse left-ventricular remodeling following acute myocardial infarction. Background Patients with hemorrhagic infarcts appear to constitute a high-risk group in acute myocardial infarction (AMI). However, the clinical implications of hemorrhagic versus non-hemorrhagic infarcts are currently unclear, warranting a more systematic and mechanistic approach towards understanding the underlying consequences. The question of whether hemorrhage is simply a bystander or contributes to additional myocardial injury remains to be investigated. The purpose of the study was to artificially induce hemorrhage in normal and infarcted (but not hemorrhagic) porcine myocardium to determine whether hemorrhage, per se, worsens prior ischemic damage. Methods