Influence of acquired obesity on coronary vessel wall late gadolinium enhancement in discordant monozygote twins.

OBJECTIVES: The aim of this study was to investigate the impact of BMI on late gadolinium enhancement (LGE) of the coronary artery wall in identical monozygous twins discordant for BMI. Coronary LGE represents a useful parameter for the detection and quantification of atherosclerotic coronary vessel wall disease. METHODS: Thirteen monozygote female twin pairs (n = 26) with significantly different BMIs (>1.6 kg/m2) were recruited out of >10,000 twin pairs (TwinsUK Registry). A coronary 3D-T2prep-TFE MR angiogram and 3D-IR-TFE vessel wall scan were performed prior to and following the administration of 0.2 mmol/kg of Gd-DTPA on a 1.5 T MR scanner. The number of enhancing coronary segments and contrast to noise ratios (CNRs) of the coronary wall were quantified. RESULTS: An increase in BMI was associated with an increased number of enhancing coronary segments (5.3 ± 1.5 vs. 3.5 ± 1.6, p < 0.0001) and increased coronary wall enhancement (6.1 ± 1.1 vs. 4.8 ± 0.9, p = 0.0027) compared to matched twins with lower BMI. CONCLUSIONS: This study in monozygous twins indicates that acquired factors predisposing to obesity, including lifestyle and environmental factors, result in increased LGE of the coronary arteries, potentially reflecting an increase in coronary atherosclerosis in this female study population. KEY POINTS: • BMI-discordant twins allow the investigation of the influence of lifestyle factors independent from genetic confounders. • Only thirteen obesity-discordant twins were identified underlining the strong genetic component of BMI. • In female twins, a BMI increase is associated with increased coronary late gadolinium enhancement. • Increased late gadolinium enhancement in the coronary vessel wall potentially reflects increased atherosclerosis.

Single breath-hold assessment of cardiac function using an accelerated 3D single breath-hold acquisition technique--comparison of an intravascular and extravascular contrast agent.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is the current gold standard for the assessment of left ventricular (LV) function. Repeated breath-holds are needed for standard multi-slice 2D cine steady-state free precession sequences (M2D-SSFP). Accelerated single breath-hold techniques suffer from low contrast between blood pool and myocardium. In this study an intravascular contrast agent was prospectively compared to an extravascular contrast agent for the assessment of LV function using a single-breath-hold 3D-whole-heart cine SSFP sequence (3D-SSFP). METHODS: LV function was assessed in fourteen patients on a 1.5 T MR-scanner (Philips Healthcare) using 32-channel coil technology. Patients were investigated twice using a 3D-SSFP sequence (acquisition time 18-25 s) after Gadopentetate dimeglumine (GdD, day 1) and Gadofosveset trisodium (GdT, day 2) administration. Image acquisition was accelerated using sensitivity encoding in both phase encoding directions (4xSENSE). CNR and BMC were both measured between blood and myocardium. The CNR incorporated noise measurements, while the BMC represented the coeffiancy between the signal from blood and myocardium [1]. Contrast to noise ratio (CNR), blood to myocardium contrast (BMC), image quality, LV functional parameters and intra-/interobserver variability were compared. A M2D-SSFP sequence was used as a reference standard on both days. RESULTS: All 3D-SSFP sequences were successfully acquired within one breath-hold after GdD and GdT administration. CNR and BMC were significantly (p < 0.05) higher using GdT compared to GdD, resulting in an improved endocardial definition. Using 3D-SSFP with GdT, Bland-Altman plots showed a smaller bias (95% confidence interval LVEF: 9.0 vs. 23.7) and regression analysis showed a stronger correlation to the reference standard (R2 = 0.92 vs. R2 = 0.71), compared to 3D-SSFP with GdD. CONCLUSIONS: A single-breath-hold 3D-whole-heart cine SSFP sequence in combination with 32-channel technology and an intravascular contrast agent allows for the accurate and fast assessment of LV function.

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.

In vivo MR-angiography for the assessment of aortic aneurysms in an experimental mouse model on a clinical MRI scanner: Comparison with high-frequency ultrasound and histology.

BACKGROUND: MR-angiography currently represents one of the clinical reference-standards for the assessment of aortic-dimensions. For experimental research in mice, dedicated preclinical high-field MRI scanners are used in most studies. This type of MRI scanner is not available in most institutions. The aim of this study was to evaluate the potential of MR-angiography performed on a clinical MR scanner for the assessment of aortic aneurysms in an experimental mouse model, compared to a preclinical high-resolution ultrasound imaging system and histopathology. METHODS: All in vivo MR imaging was performed with a clinical 3T MRI system (Philips Achieva) equipped with a clinical gradient system in combination with a single-loop surface-coil (47 mm). All MR sequences were based on clinically used sequences. For ultrasound, a dedicated preclinical high-resolution system (30 MHz linear transducer, Vevo770, VisualSonics) was used. All imaging was performed with an ApoE knockout mouse-model for aortic aneurysms. Histopathology was performed as reference-standard at all stages of aneurysm development. RESULTS: MR-angiography on a clinical 3T system enabled the clear visualization of the aortic lumen and aneurysmal dilation at different stages of aneurysm development. A close correlation (R2 = 0.98; p < 0.001) with histological area measurements was found. Additionally, a good agreement between MR and ultrasound area measurements in systole (R2 = 0.91; p < 0.001) and diastole (R2 = 0.94; p < 0.001) were measured. Regarding interobserver reproducibility, MRI measurements yielded a smaller 95% confidence interval and a closer interreader correlation compared to ultrasound measurements (-0.37-0.46; R2 = 0.97 vs. -0.78-0.88; R2 = 0.87). CONCLUSION: This study demonstrates that MR-angiography, performed on a clinical 3T MR scanner, enables the reliable detection and quantification of the aortic dilatation at different stages of aneurysm development in an experimental mouse model.

In Vivo High-Frequency Ultrasound for the Characterization of Thrombi Associated with Aortic Aneurysms in an Experimental Mouse Model.

The development of abdominal aortic aneurysm (AAA) associated thrombi plays an important role during the onset and progression of AAAs. The aim of this study was to evaluate the potential of high-frequency ultrasound for characterization of AAA associated thrombi in an apolipoprotein-E-deficient mouse-model. Ultrasound measurements were performed using a high-resolution ultrasound system (Vevo770, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) with a 30 MHz linear-array transducer (RMV707 B). Magnetic resonance imaging with a 3 Tesla scanner (Achieva MR system, Philips Healthcare, Best, The Netherlands) and a single-loop microscopy coil was performed as a reference standard. All stages of aneurysm development were evaluated by histologic analyses. The "signal-thrombus-matrix" to "signal-blood" ratio on high-frequency ultrasound measurements showed a strong correlation (R2 = 0.81, p <0.05) with the state of extracellular matrix remodeling. Furthermore, size measurements derived from the high-frequency ultrasound correlated well with magnetic resonance imaging and histology. This study demonstrated that high-frequency ultrasound enables the reliable in vivo quantification of extracellular matrix remodeling at various stages of thrombus development, based on the thrombus echogenicity.

Contrast-enhanced magnetic resonance imaging for the detection of ruptured coronary plaques in patients with acute myocardial infarction.

PURPOSE: X-ray coronary angiography (XCA) is the current gold standard for the assessment of lumen encroaching coronary stenosis but XCA does not allow for early detection of rupture-prone vulnerable plaques, which are thought to be the precursor lesions of most acute myocardial infarctions (AMI) and sudden death. The aim of this study was to investigate the potential of delayed contrast-enhanced magnetic resonance coronary vessel wall imaging (CE-MRCVI) for the detection of culprit lesions in the coronary arteries. METHODS: 16 patients (13 male, age 61.9±8.6 years) presenting with sub-acute MI underwent CE-MRCVI within 24-72h prior to invasive XCA. CE-MRCVI was performed using a T1-weighted 3D gradient echo inversion recovery sequence (3D IR TFE) 40±4 minutes following the administration of 0.2 mmol/kg gadolinium-diethylenetriamine-pentaacetic acid (DTPA) on a 3T MRI scanner equipped with a 32-channel cardiac coil. RESULTS: 14 patients were found to have culprit lesions (7x LAD, 1xLCX, 6xRCA) as identified by XCA. Quantitative CE-MRCVI correctly identified the culprit lesion location with a sensitivity of 79% and excluded culprit lesion formation with a specificity of 99%. The contrast to noise ratio (CNR) of culprit lesions (9.7±4.1) significantly exceeded CNR values of segments without culprit lesions (2.9±1.9, p<0.001). CONCLUSION: CE-MRCVI allows the selective visualization of culprit lesions in patients immediately after myocardial infarction (MI). The pronounced contrast uptake in ruptured plaques may represent a surrogate biomarker of plaque activity and/or vulnerability.

In vivo assessment of aortic aneurysm wall integrity using elastin-specific molecular magnetic resonance imaging.

BACKGROUND: The incidence of abdominal aortic aneurysms (AAAs) has increased during the last decades. However, there is still controversy about the management of medium-sized AAAs. Therefore, novel biomarkers, besides aneurysmal diameter, are needed to assess aortic wall integrity and risk of rupture. Elastin is the key protein for maintaining aortic wall tensile strength and stability. The progressive breakdown of structural proteins, in particular, medial elastin, is responsible for the inability of the aortic wall to withstand intraluminal hemodynamic forces. Here, we evaluate the usefulness of elastin-specific molecular MRI for the in vivo characterization of AAAs. METHODS AND RESULTS: To induce AAAs, ApoE(-/-) mice were infused with angiotensin-II. An elastin-specific magnetic resonance molecular imaging agent (ESMA) was administered after 1, 2, 3, and 4 weeks of angiotensin-II infusion to assess elastin composition of the aorta (n=8 per group). The high signal provided by ESMA allowed for imaging with high spatial resolution, resulting in an accurate assessment of ruptured elastic laminae and the compensatory expression of elastic fibers. In vivo contrast-to-noise ratios and R1-relaxation rates after ESMA administration were in good agreement with ex vivo histomorphometry (Elastica van Gieson stain) and gadolinium concentrations determined by inductively coupled plasma mass spectroscopy. Electron microscopy confirmed colocalization of ESMA with elastic fibers. CONCLUSIONS: Changes in elastin content could be readily delineated and quantified at different stages of AAAs by elastin-specific molecular magnetic resonance imaging. ESMA-MRI offers potential for the noninvasive detection of the aortic rupture site prior to dilation of the aorta and the subsequent in vivo monitoring of compensatory repair processes during the progression of AAAs.

Platelets in cardiovascular imaging.

Coronary artery disease remains a major hazard within the western world despite early revascularisation and advanced medical therapy strategies. One of its major substrates is platelet activation and thrombus formation, triggering acute events such as myocardial infarction and ischemic strokes. There are a variety of non-invasive imaging strategies being translated from bench to bedside into clinical practice that tackle specific aspects of the pathophysiology of thrombus formation. Some of those techniques are able to visualize native contrast differences between thrombus and surrounding tissue, others focus on the use of specific contrast agents targeting thrombotic components such as fibrin or activated platelets. Some of those techniques are still in the pre-clinical stage; others have already entered the clinical arena. The current review article will introduce different techniques and their stage of development on their way from bench to bedside with a specific focus on cardiac magnetic resonance imaging, that has evolved over the last years providing high quality information on anatomy, perfusion and myocardial tissue characteristics such as scarring in clinical practice. Finally, we will give an outlook on how this exciting field might evolve in the future.

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.

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 µmol 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 (R(2)=0.70, P<0.05) and the macrophage density (R(2)=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.

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 MRI in small animals.

Imaging studies of cardiovascular disease in small rodents have become a prerequisite in preclinical cardiovascular research. Transgenic and gene-knockout models of cardiovascular diseases enables the investigation of the influence of single genes or groups of genes on disease pathogenesis. In addition, experimental and genetically altered models provide valuable in vivo platforms to investigate the efficacy of novel drugs and contrast agents. Owing to the excellent soft tissue contrast, high spatial and temporal resolution, as well as the tomographic nature of MRI, anatomy and function can be assessed with unique accuracy and reproducibility. Furthermore, using novel targeted MRI contrast agents, molecular changes associated with cardiovascular disease can be investigated in the same imaging session. This review focuses on recent advances in hardware, imaging sequences and probe design.

Molecular imaging with targeted contrast agents.

Molecular imaging with targeted contrast agents by magnetic resonance imaging (MRI) allows for the noninvasive detection and characterization of biological changes on a molecular level. In this article, the principles of molecular MRI and its applications in cardiovascular diseases are reviewed. First, basic properties of positive and negative contrast agents are introduced and their effect on signal generation in a magnetic field is described. In the next part, different types of MRI scanners and the influence of field strength on signal properties of contrast agents for molecular imaging are discussed. Additionally, the assessment, analysis, and quantification of the changes in T1 and T2* relaxation time induced by the different molecular contrast agents are reviewed. Finally, the basic mechanisms of targeting of imaging probes on a molecular level and recent applications of molecular MRI in cardiovascular disease are reviewed.