Marcus R. Makowski

Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent

Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Plaque burden and progression have been shown to be independent predictors for future cardiac events by intravascular ultrasound. Routine prospective imaging is hampered by the invasive nature of intravascular ultrasound. A noninvasive technique would therefore be more suitable for screening of atherosclerosis in large populations. Here we introduce an elastin-specific magnetic resonance contrast agent (ESMA) for noninvasive quantification of plaque burden in a mouse model of atherosclerosis. The strong signal provided by ESMA allows for imaging with high spatial resolution, resulting in accurate assessment of plaque burden. Additionally, plaque characterization by quantifying intraplaque elastin content using signal intensity measurements is possible. Changes in elastin content and the high abundance of elastin during plaque development, in combination with the imaging properties of ESMA, provide potential for noninvasive assessment of plaque burden by molecular magnetic resonance imaging (MRI).

Cardiovascular magnetic resonance myocardial feature tracking detects quantitative wall motion during dobutamine stress

BackgroundDobutamine stress cardiovascular magnetic resonance (DS-CMR) is an established tool to assess hibernating myocardium and ischemia. Analysis is typically based on visual assessment with considerable operator dependency. CMR myocardial feature tracking (CMR-FT) is a recently introduced technique for tissue voxel motion tracking on standard steady-state free precession (SSFP) images to derive circumferential and radial myocardial mechanics.We sought to determine the feasibility and reproducibility of CMR-FT for quantitative wall motion assessment during intermediate dose DS-CMR.Methods10 healthy subjects were studied at 1.5 Tesla. Myocardial strain parameters were derived from SSFP cine images using dedicated CMR-FT software (Diogenes MRI prototype; Tomtec; Germany). Right ventricular (RV) and left ventricular (LV) longitudinal strain (EllRV and EllLV) and LV long-axis radial strain (ErrLAX) were derived from a 4-chamber view at rest. LV short-axis circumferential strain (EccSAX) and ErrSAX; LV ejection fraction (EF) and volumes were analyzed at rest and during dobutamine stress (10 and 20 μg · kg-1· min-1).ResultsIn all volunteers strain parameters could be derived from the SSFP images at rest and stress. EccSAX values showed significantly increased contraction with DSMR (rest: -24.1 ± 6.7; 10 μg: -32.7 ± 11.4; 20 μg: -39.2 ± 15.2; p < 0.05). ErrSAX increased significantly with dobutamine (rest: 19.6 ± 14.6; 10 μg: 31.8 ± 20.9; 20 μg: 42.4 ± 25.5; p < 0.05). In parallel with these changes; EF increased significantly with dobutamine (rest: 56.9 ± 4.4%; 10 μg: 70.7 ± 8.1; 20 μg: 76.8 ± 4.6; p < 0.05). Observer variability was best for LV circumferential strain (EccSAX ) and worst for RV longitudinal strain (EllRV) as determined by 95% confidence intervals of the difference.ConclusionsCMR-FT reliably detects quantitative wall motion and strain derived from SSFP cine imaging that corresponds to inotropic stimulation. The current implementation may need improvement to reduce observer-induced variance. Within a given CMR lab; this novel technique holds promise of easy and fast quantification of wall mechanics and strain.

In vivo molecular imaging of angiogenesis, targeting αvβ3 integrin expression, in a patient after acute myocardial infarction

A 35-year-old Caucasian male presented with chest pain and nausea in the emergency room. The initial ECG displayed sinus-rhythm with ST elevation in I, aVL, V1–5, ST-depression in III, and aVR and pathological Q waves in V1–5. The laboratory results showed severely elevated cardiac enzymes. Percutaneous coronary intervention (PCI) with stenting of the completely occluded proximal left anterior descending (LAD) was performed without complications. Two weeks after the myocardial infarction and PCI, the patient underwent MRI and PET/CT evaluation …

The intra-observer reproducibility of cardiovascular magnetic resonance myocardial feature tracking strain assessment is independent of field strength

BACKGROUND Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a promising novel method for quantification of myocardial wall mechanics from standard steady-state free precession (SSFP) images. We sought to determine whether magnetic field strength affects the intra-observer reproducibility of CMR-FT strain analysis. METHODS We studied 2 groups, each consisting of 10 healthy subjects, at 1.5 T or 3T Analysis was performed at baseline and after 4 weeks using dedicated CMR-FT prototype software (Tomtec, Germany) to analyze standard SSFP cine images. Right ventricular (RV) and left ventricular (LV) longitudinal strain (Ell(RV) and Ell(LV)) and LV long-axis radial strain (Err(LAX)) were derived from the 4-chamber cine, and LV short-axis circumferential and radial strains (Ecc(SAX), Err(SAX)) from the short-axis orientation. Strain parameters were assessed together with LV ejection fraction (EF) and volumes. Intra-observer reproducibility was determined by comparing the first and the second analysis in both groups. RESULTS In all volunteers resting strain parameters were successfully derived from the SSFP images. There was no difference in strain parameters, volumes and EF between field strengths (p>0.05). In general Ecc(SAX) was the most reproducible strain parameter as determined by the coefficient of variation (CV) at 1.5 T (CV 13.3% and 46% global and segmental respectively) and 3T (CV 17.2% and 31.1% global and segmental respectively). The least reproducible parameter was Ell(RV) (CV 1.5 T 28.7% and 53.2%; 3T 43.5% and 63.3% global and segmental respectively). CONCLUSIONS CMR-FT results are similar with reasonable intra-observer reproducibility in different groups of volunteers at 1.5 T and 3T. CMR-FT is a promising novel technique and our data indicate that results might be transferable between field strengths. However there is a considerable amount of segmental variability indicating that further refinements are needed before CMR-FT can be fully established in clinical routine for quantitative assessment of wall mechanics and strain.

Detection of intracoronary thrombus by magnetic resonance imaging in patients with acute myocardial infarction.

Background— Persistent intracoronary thrombus after plaque rupture is associated with an increased risk of subsequent myocardial infarction and mortality. Coronary thrombus is usually visualized invasively by x-ray coronary angiography. Non–contrast-enhanced T1-weighted magnetic resonance (MR) imaging has been useful for direct imaging of carotid thrombus and intraplaque hemorrhage by taking advantage of the short T1 of methemoglobin present in acute thrombus and intraplaque hemorrhage. The aim of this study was to investigate the use of non–contrast–enhanced MR for direct thrombus imaging (MRDTI) in patients with acute myocardial infarction. Methods and Results— Eighteen patients (14 men; age, 61±9 years) underwent MRDTI within 24 to 72 hours of presenting with an acute coronary syndrome before invasive x-ray coronary angiography; MRDTI was performed with a T1-weighted, 3-dimensional, inversion-recovery black-blood gradient-echo sequence without contrast administration. Ten patients were found to have intracoronary thrombus on x-ray coronary angiography (left anterior descending, 4; left circumflex, 2; right coronary artery, 4; and right coronary artery–posterior descending artery, 1), and 8 had no visible thrombus. We found that MRDTI correctly identified thrombus in 9 of 10 patients (sensitivity, 91%; posterior descending artery thrombus not detected) and correctly classified the control group in 7 of 8 patients without thrombus formation (specificity, 88%). The contrast-to-noise ratio was significantly greater in coronary segments containing thrombus (n=10) compared with those without visible thrombus (n=131; mean contrast-to-noise ratio, 15.9 versus 2.6; P<0.001). Conclusion— Use of MRDTI allows selective visualization of coronary thrombus in a patient population with a high probability of intracoronary thrombosis.

MRI of Coronary Wall Remodeling in a Swine Model of Coronary Injury Using an Elastin-Binding Contrast Agent

Background—The extracellular matrix (ECM) plays an important role in the pathogenesis of atherosclerosis and in-stent restenosis. Elastin is an essential component of the ECM. ECM degradation can lead to plaque destabilization, whereas enhanced synthesis typically leads to vessel wall remodeling resulting in arterial stenosis or in-stent restenosis after stent implantation. The objective of this study was to demonstrate the feasibility of MRI of vascular remodeling using a novel elastin-binding contrast agent (BMS-753951). Methods and Results—Coronary injury was induced in 6 pigs by endothelial denudation and stent placement. At day 28, delayed-enhancement MRI coronary vessel wall imaging was performed before and after injection of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA). Two days later, DE-MRI was repeated after administration of BMS-753951. Contrast-to-noise-ratio and areas of enhancement were determined. Delayed-enhancement MRI with BMS-753951 caused strong enhancement of the aortic, pulmonary artery, and injured coronary artery walls, whereas Gd-DTPA did not. Delayed-enhancement MRI of the stented coronary artery with BMS-753951 yielded a 3-fold higher contrast-to-noise-ratio when compared with the balloon-injured and control coronary artery (21±6 versus 7±3 versus 6±4; P<0.001). The area of enhancement correlated well with the area of remodeling obtained from histological data (R2=0.86, P<0.05). Conclusions—We demonstrate the noninvasive detection and quantification of vascular remodeling in an animal model of coronary vessel wall injury using an elastin-specific MR contrast agent. This novel approach may be useful for the assessment of coronary vessel wall remodeling in patients with suspected coronary artery disease. Further studies in atherosclerotic animal models and degenerative ECM disease are now warranted.

First-Pass Contrast-Enhanced Myocardial Perfusion MRI in Mice on a 3-T Clinical MR Scanner

First‐pass contrast‐enhanced myocardial perfusion MRI in rodents has so far not been possible due to the temporal and spatial resolution requirements. We developed a new first‐pass perfusion MR method for rodent imaging on a clinical 3.0‐T scanner (Philips Healthcare, Best, The Netherlands) that employed 10‐fold k‐space and time domain undersampling with constrained image reconstruction, using temporal basis sets (k‐t principle component analysis) to achieve a spatial resolution of 0.2 × 0.2 × 1.5mm3 and an acquisition window of 43 msec. The method was successfully tested in five healthy and four infarcted mice (C57BL/6J) at heart rates of 495.1 ± 45.8 beats/min. Signal‐intensity‐time profiles showed a percentage myocardial signal increase of 141.3 ± 38.9% in normal mice, compared with 44.7 ± 32.4% in infarcted segments. Mean myocardial blood flow by Fermi function for constrained deconvolution in control mice was 7.3 ± 1.5 mL/g/min, comparable to published literature, with no significant differences between three myocardial segments. In infarcted segments, myocardial blood flow was significantly reduced to 1.2 ± 0.8 mL/g/min (P < 0.01). This is the first report of first‐pass myocardial perfusion MR in a mouse model on a clinical 3‐T MR scanner and using a k‐t undersampling method. Data were acquired on a 3‐T scanner, using an approach similar to clinical acquisition protocols, thus facilitating translation of imaging findings between rodent and human studies. Magn Reson Med, 2010.

Noninvasive Assessment of Atherosclerotic Plaque Progression in ApoE(-/-) Mice Using Susceptibility Gradient Mapping

Background— Macrophages have been identified as a major contributor to plaque development and destabilization in atherosclerosis. The aim of this study was to noninvasively assess uptake of citrate coated very small iron oxide particles at different stages of plaque development in the brachiocephalic artery of apoE−/− mice. Susceptibility gradient mapping (SGM) was applied to generate positive contrast images and to quantify iron oxide uptake. Methods and Results— ApoE−/− mice were fed a high-fat diet for 4, 8, or 12 weeks; 300 &mgr;mol Fe/kg was injected 24 and 48 hours before final MRI. Increasing very small iron oxide particle uptake was observed over the course of atherosclerotic plaque development. Simultaneous administration of pravastatin led to a significant decrease in very small iron oxide particle uptake, assessed by mass spectroscopy and histology. SGM-MRI allowed the generation of positive contrast images, and magnitudes (mT/m) of contrast enhancement in SG parameter maps significantly correlated with the absolute iron oxide content (R2=0.70, P<0.05) and the macrophage density (R2=0.71, P<0.05). Conclusions— This study shows an increase in iron oxide uptake (measured by in vivo SGM-MRI, histology, and mass spectroscopy) with the progression of plaque development in an apoE−/− mouse model of accelerated atherosclerosis. Positive contrast provided by SGM-MRI allowed for a clear visualization of intraplaque iron oxide depositions, and magnitudes (mT/m) of contrast enhancement in SG parameter maps allowed for the quantification of intraplaque iron oxide particles.

In vivo assessment of intraplaque and endothelial fibrin in ApoE−/− mice by molecular MRI

OBJECTIVE Molecular magnetic resonance imaging (MRI) has emerged as a promising non-invasive modality to characterize atherosclerotic vessel wall changes on a morphological and molecular level. Intraplaque and endothelial fibrin has recently been recognized to play an important role in the progression of atherosclerosis. This study aimed to investigate the feasibility of intraplaque and endothelial fibrin detection using a fibrin-targeted contrast-agent, FTCA (EPIX Pharmaceuticals, Lexington, MA), in a mouse model of atherosclerosis. METHODS Male apolipoproteinE-knockout mice (ApoE(-/-)) were fed a high fat diet (HFD) for one to three months. MRI of the brachiocephalic artery was performed prior to and 90 min after the administration of FTCA (n=8 per group). Contrast to noise ratios (CNR) and longitudinal relaxation rates (R1) of plaques were determined and compared to ex vivo fibrin density measurements on immunohistological sections stained with a fibrin-specific antibody and gadolinium concentrations measured by inductively coupled mass spectroscopy (ICP-MS). RESULTS Molecular MRI after FTCA administration demonstrated a significant increase (p<0.05) in contrast agent uptake in brachiocephalic artery plaques. In vivo CNR measurements were in good agreement with ex vivo fibrin density measurements on immunohistochemistry (y=2.4x+11.3, R(2)=0.82) and ICP-MS (y=0.95x+7.1, R(2)=0.70). Late stage atherosclerotic plaques displayed the strongest increase in CNR, R1, ex vivo fibrin staining and gadolinium concentration (p<0.05). CONCLUSION This study demonstrated the feasibility of intraplaque and endothelial fibrin imaging using FTCA. Direct in vivo fibrin detection and quantification could be useful for characterization and staging of coronary and carotid atherosclerotic lesions, which may aid diagnosis and intervention.

Congenital Heart Disease: Cardiovascular MR Imaging by Using an Intravascular Blood Pool Contrast Agent

PURPOSE To compare the image quality and diagnostic performance of a contrast agent-specific inversion-recovery (IR) steady-state free precession (SSFP) magnetic resonance (MR) imaging sequence performed by using an intravascular contrast agent (gadofosveset trisodium) with those of a commonly used T2-prepared SSFP sequence performed by using an extravascular (gadopentetate dimeglumine) and an intravascular (gadofosveset trisodium) contrast agent in patients with congenital heart disease (CHD). MATERIALS AND METHODS The local ethics committee and the United Kingdom Medicines and Healthcare products Regulatory Agency approved this study. Patient informed consent was obtained. Twenty-three patients with CHD were examined by using a 1.5-T MR imaging unit and a 32-channel coil. Gadopentetate dimeglumine and gadofosveset trisodium were used in the same patient on consecutive days. Vessel wall sharpness, contrast-to-noise ratios (CNRs), image quality, and diagnostic performance achieved by using the IR SSFP sequence with gadofosveset trisodium were compared with those achieved by using the T2-prepared SSFP sequence with gadopentetate dimeglumine and gadofosveset trisodium and with those achieved at respective contrast material-enhanced MR angiographic examinations. The Wilcoxon rank sum test was used to compare categoric variables; t tests were used to compare continuous variables. RESULTS Use of the IR SSFP sequence with gadofosveset trisodium significantly improved vessel wall sharpness, CNRs, and image quality (P < .05 for all) for all investigated intra- and extracardiac structures compared with the T2-prepared SSFP sequence with gadopentetate dimeglumine and gadofosveset trisodium and the respective contrast-enhanced MR angiographic examinations. With use of the IR SSFP sequence with gadofosveset trisodium, new, unsuspected diseases (five [22%] of 23) were diagnosed, while other diseases could be excluded (15 [65%] of 23). Information available from echocardiography (n = 23), conventional angiography (n = 4), and/or surgery (n = 1) confirmed all diagnoses. CONCLUSION IR SSFP with gadofosveset trisodium improved image quality and diagnostic performance, allowing a more accurate and complete assessment of cardiovascular anatomy in patients with CHD compared with T2-prepared SSFP with gadopentetate dimeglumine and gadofosveset trisodium and respective contrast-enhanced MR angiographic examinations.