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Fulminant myocarditis is rare but a potentially life-threatening disease. Acute or mild myocarditis following acute ischemia is generally associated with a profound activation of the host’s immune system. On one hand this is mandatory to protect the host’s heart by fighting the invading agents (i.e., bacteria, viruses or other microbial agents) and/or to induce healing and repair processes in the damaged myocardium. On other hand, uncontrolled activation of the immune system may result in the generation of auto-reactive (not always beneficial) immune cells.
Myocarditis or inflammatory cardiomyopathy is characterized by focal or diffuse infiltrates, myocyte necrosis and/or apoptosis and subsequent fibrotic replacement of the heart muscle. In humans, about 30% of the myocarditis-patients develop dilated cardiomyopathy. As the clinical picture of myocarditis is multifaceted, it is difficult to diagnose the disease. Therefore, the main goal of the present work was to test and further develop novel non-invasive methods for the detection of myocardial inflammation by employing both contrast enhanced MRI techniques as well as novel nuclear tracers that are suitable for in vivo PET/ SPECT imaging.
As a part of this thesis, a pre-clinical animal model was successfully established by immunizing female Lewis rats with whole-porcine cardiac myosin (CM). Induction of Experimental Autoimmune Myocarditis (EAM) is considered successful when anti-myosin antibody titers are increased more than 100-fold over control animals and pericardial effusion develops. In addition, cardiac tissues from EAM-rats versus controls were analyzed for the expression of various pro-inflammatory and fibrosis markers. To further exploit non-invasive MRI techniques for the detection of myocarditis, our EAM-rats were injected either with (1) ultra-small Paramagnetic iron oxide particles (USPIO’s; Feraheme®), allowing for in vivo imaging , (2) micron sized paramagnetic iron oxide particles (MPIO) for ex vivo inflammatory cell-tracking by cMRI, or (3) with different radioactive nuclear tracers (67gallium citrate, 68gallium-labeled somatostatin analogue, and 68gallium-labeled cyclic RGD-peptide) which in the present work have been employed for autoradiographic imaging, but in principle are also suitable for in vivo nuclear imaging (PET/SPECT). In order to compare imaging results with histology, consecutive heart sections were stained with hematoxylin & eosin (HE, for cell infiltrates) and Masson Goldner trichrome (MGT, for fibrosis); in addition, immuno-stainings were performed with anti-CD68 (macrophages), anti-SSRT2A (somatostatin receptor type 2A), anti-CD61 (β3-integrins) and anti-CD31 (platelet endothelial cell adhesion molecule 1).
Sera from immunized rats strongly reacted with cardiac myosin. In immunized rats, echocardiography and subsequent MRI revealed huge amounts of pericardial effusion (days 18-21). Analysis of the kinetics of myocardial infiltrates revealed maximal macrophage invasion between days 14 and 28. Disappearance of macrophages resulted in replacement-fibrosis in formerly cell-infiltrated myocardial areas. This finding was confirmed by the time-dependent differential expression of corresponding cytokines in the myocardium. Immunized animals reacted either with an early or a late pattern of post-inflammation fibrosis. Areas with massive cellular infiltrates were easily detectible in autoradiograms showing a high focal uptake of 67gallium-citrate and 68gallium labeled somatostatin analogues (68Ga DOTA-TATE). Myocardium with a loss of cardiomyocytes presented a high uptake of 68gallium labeled cyclic RGD-peptide (68Ga NOTA-RGD). MRI cell tracking experiments with Feraheme® as the contrast-agent were inconclusive; however, strikingly better results were obtained when MPIOs were used as a contrast-agent: histological findings correlated well with in vivo and ex vivo MPIO-enhanced MRI images.
Imaging of myocardial inflammatory processes including the kinetics of macrophage invasion after microbial or ischemic damage is still a major challenge in, both animal models and in human patients. By applying a broad panel of biochemical, histological, molecular and imaging methods, we show here that different patterns of reactivity may occur upon induction of myocarditis using one and the same rat strain. In particular, immunized Lewis rats may react either with an early or a late pattern of macrophage invasion and subsequent post-inflammation fibrosis. Imaging results achieved in the acute inflammatory phase of the myocarditis with MPIOs, 67gallium citrate and 68gallium linked to somatostatin will stimulate further development of contrast agents and radioactive-nuclear tracers for the non-invasive detection of acute myocarditis and in the near future perhaps even in human patients.
Magnetic resonance imaging is derogated by the presence of metal implants and image quality is impaired. Artifacts are categorized according to their sources, the differences in susceptibility between metal and tissue and the modulation of the magnetic radiofrequency (RF) transmit field. Generally, these artifacts are intensified at higher field strength. The purpose of this work is to analyze the efficiency of current methods used for metal artifact reduction at 3T and to investigate improvements. The impact of high-bandwidth RF pulses on susceptibility-induced artifacts is tested. In addition, the benefit of a two-channel transmit system with respect to shading close to total hip replacements and other elongated metal structures in parallel to the magnetic field is analyzed.
Local transmit/receive coils feature a higher peak B1 amplitude than conventional body coils and thus enable high-bandwidth RF pulses. Susceptibility-induced through-plane distortion relates reciprocally to the RF bandwidth, which is evaluated in vitro for a total knee arthroplasty. Clinically relevant sequences (TSE and SEMAC) with conventional and high RF pulse bandwidths and different contrasts are tested on eight patients with different types of knee implants. Distortion is rated by two radiologists. An additional analysis assesses the capability of a local spine transmit coil. Furthermore, B1 effects close to elongated metal structures are described by an analytical model comprising a water cylinder and a metal rod, which is verified numerically and experimentally. The dependence of the optimal polarization of the transmit B1 field, creating minimum shading, on the position of the metal is analyzed. In addition, the optimal polarization is determined for two patients; its benefit compared to circular polarization is assessed.
Phantom experiments confirm the relation of the RF bandwidth and the through-plane distortion, which can be reduced by up to 79% by exploitation of a commercial local transmit/receive knee coil at 3T. On average, artifacts are rated “hardly visible” for patients with joint arthroplasties, when high-bandwidth RF pulses and SEMAC are used, and for patients with titanium fixtures, when high-bandwidth RF pulses are used in combination with TSE. The benefits of the local spine transmit coil are less compared to the knee coil, but enable a bandwidth 3.9 times as high as the body coil. The modulation of B1 due to metal is approximated well by the model presented and the position of the metal has strong influence on this effect. The optimal polarization can mitigate shading substantially.
In conclusion, through-plane distortion and related artifacts can be reduced significantly by the application of high-bandwidth RF pulses by local transmit coils at 3T. Parallel transmission offers an option to substantially reduce shading close to long metal structures aligned with the magnetic field. Effective techniques dedicated for metal implant imaging at 3T are introduced in this work.