Abstract Background Recently, we established an experimental model of moderate aortic valve stenosis (AS) aiming to mimic human disease progression closely. Functional and structural MRI of a mouse model in experimental aortic valve stenosis has not been accomplished so far. Purpose Here, we aimed at developing comprehensive MRI approach for simultaneous assessment of changes in valvular, left ventricular and aortic morphology and function. Methods Male 12-week-old wildtype mice (C57Bl/6) were subjected to wire injury of the aortic valve to induce aortic valve stenosis. High resolution MRI at 9.4T was used to monitor subsequent functional and structural changes in the aortic valve, the ascending aorta, the left ventricle and aortic flow patterns. Results MRI permits accurate planimetry of the orifice and the thickness of the aortic valve, allows a reliable three-dimensional mapping of transvalvular aortic flow, simultaneously depicts aortic regurgitation in 3D fashion and permits assessment of left ventricular changes due to AS. In our model we observed a reduced valve orifice and an increase in valve thickness. Homogenous flow pattern under control converted to heterogenous and turbulent flow with progression of AS associated with increased aortic strain, aortic wall and left ventricular wall thickness. Conclusions In a murine model of aortic valve stenosis MRI is capable to reliably display a three-dimensional transvalvular aortic flow profile with concomitant quantification of structural and functional changes in aortic valve, left ventricle, and ascending aorta. This comprehensive functional imaging at high resolution and distinct reproducibility offers for the first time serial assessment of disease progression in an experimental model of aortic valve stenosis.

BACKGROUND:Patients with severe aortic stenosis (AS) are subjected to left ventricular hypertrophy (LVH) with increasing morbidity and mortality. Transcatheter aortic valve replacement (TAVR) induces reverse left ventricular remodeling which can be monitored by cardiovascular magnetic resonance (CMR). CMR is able to analyze myocardial tissue properties by magnetic relaxation times (parametric CMR). The objective of this study was to study myocardial T2 relaxation in reverse ventricular remodeling after TAVR.METHODS:Forty-three patients with severe AS (19 males, 81.9 ± 4.9 years) underwent CMR with T2 mapping before and 6 months after TAVR. A cohort of age- and gender-matched volunteers served as controls. Analyzed parameters included left ventricular ejection fraction (LV-EF), mass indexed to body surface area (LVMi), interventricular septum thickness (IVS), end-diastolic volume (LVEDV), global longitudinal strain (GLS), peak diastolic strain rate (SRe) and myocardial T2 values.RESULTS:CMR characteristics for patients with AS displayed LVH concomitant to elevated myocardial T2 values, reduced GLS and SRe. Patients with T2 values above 70.2 ms at baseline were characterized by eccentric hypertrophy with reduced LV-EF. T2 values decreased after TAVR (67.4 ± 3.4 to 63.3 ± 4.2 ms, p < 0.01) during left ventricular remodeling. Patients with T2 values above 70.2 ms at baseline exhibited pronounced reverse remodeling which proved to be a significant predictor of LV-EF improvement and LVEDV reduction in uni- and multivariate analyses.CONCLUSIONS:Multiparametric CMR can be used to characterize myocardial hypertrophy due to severe AS and to monitor myocardial adaptations after TAVR. It may provide additional information in the prediction of left ventricular remodeling after TAVR.

Aims The aim of this study was to determine the value of T2 mapping for the non-invasive assessment of myocardial inflammation in different stages of systolic left ventricular dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy (EMB). Methods and results A total of 132 subjects were enrolled between 2013 and 2016 (62 controls and 70 patients with DCM). All patients underwent CMR at 1.5 T and received coronary angiogram and EMB. CMR applied standard protocols including T2 mapping with Gradient And SpinEcho sequence (GRASE). Global T2 relaxation time was significantly increased in patients with DCM compared to the healthy controls (T2 time DCM vs. controls: 65.9 ± 6.2 vs. 60.0 ± 4.2 ms; P < 0.001). Of note, patients with the presence of inflammatory cells in EMB exhibited further elevation of T2 values (T2 time in patients with the presence of inflammatory cells vs. T2 time in patients without: 68.8 ± 5.8 vs. 64.7 ± 5.9 ms; P = 0.02). Receiver operating characteristic analysis of our data deciphered a global myocardial T2 time >65.3 ms as the best cut-off for distinction between the healthy controls and patients with myocardial inflammation [sensitivity 93%, specificity 90%, P < 0.01, area under the curve (AUC) 0.95]. In patients with DCM, this threshold identified patients with biopsy-proven inflammation with a sensitivity of 79% and specificity 58% (AUC 0.72). Conclusion In patients with DCM and presence of inflammatory cells in the myocardium, myocardial T2 relaxation times may help to non-invasively detect myocardial inflammation. Although there is an overlap of T2 values between patients and healthy controls, T2 mapping may facilitate the identification of patients who may benefit from EMB for therapeutic decision-making.

AIM:Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging ((19)F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an (19)F surface coil and dedicated MR sequences.METHODS AND RESULTS:Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. (19)F MRI could be acquired with an SNR of >15 using an in-plane resolution of 2 × 2 mm(2) within <20 min for both agents. Combined late gadolinium enhancement (LGE) and (19)F MRI revealed that (19)F signal was inhomogenously distributed across LGE myocardium reflecting patchy macrophage infiltration as confirmed by histology. In whole hearts, we found an apico-basal (19)F gradient within LGE-positive myocardium. The (19)F-positive volume was always smaller than LGE volume. Ex vivo experiments on isolated monocytes revealed that pig and human cells phagocytize PFCs even more avidly than mouse monocytes.CONCLUSION:This pilot study demonstrates that (19)F MRI at 3.0 T with clinically applicable PFOB is feasible, thus highlighting the potential of (19)F MRI to monitor the inflammatory response after AMI.

Non-invasive imaging of deep venous thrombi by 19F MRI using targeted perfluorcarbon nanoemulsions Sebastian Temme, Christoph Grapentin, Christine Quast, Christoph Jacoby, Zhaoping Ding, Friederike Mayenfels, Jürgen Schrader, and Ulrich Flögel Molecular Cardiology, University of Düsseldorf, Düsseldorf, NRW, Germany, Pharmaceutical Technology and Biopharmacy, University of Freiburg, Freiburg, BW, Germany, Molecular Cardiology, University of Düsseldorf, Düsseldorf, Germany, University of Freiburg, Freiburg, BW, Germany

Background: Remote ischemic preconditioning (remote IPC) induced by short non-deleterious ischemic episodes prior to an index ischemic event is known to protect the heart from lethal myocardial ischemia-reperfusion (I/R) injury.Although demonstrated to be effective across almost all species, the underlying signaling pathways and specifically a role for nitric oxide (NO) remain poorly understood.We and others recently showed that brief episodes of limb I/R via blood pressure cuff in-/deflations increases endothelial NO synthase (eNOS) activity with a subsequent formation of NO, nitroso species (RNO) and nitrite.Nitrite, in turn, has been shown to protect the myocardium from lethal ischemia-reperfusion when activated by the heme globin myoglobin (Mb).We therefore hypothesized that remote IPC initiates the release of NO species in an eNOS-dependent manner, and that Mb is required to reduce this endogenously formed species to NO to protect the myocardium.Methods and Results: This study was conducted using a mouse model of remote IPC followed by open-chest I/R via reversible ligation of the left coronary artery in vivo.Four cycles of remote IPC consisting of 5 minutes of hindlimb ischemia followed by 5 minutes of reperfusion, checked by laser Doppler perfusion imaging, caused a release of NO, RNO and nitrite into the circulation.Remote IPC furthermore stimulated a post-translational modification of mitochondrial complex I by S-nitrosation and a subsequent decrease in reactive oxygen species in the reperfused myocardium.This finally caused a reduction in myocardial infarct size per area at risk from 36±2% to 17±1% in wild-types (n=5,p<0.0001).Targeted disruption of endothelial nitric oxide synthase in eNOS-/-mice impaired the release of NO species during remote IPC and completely abolished the beneficial effects on myocardial necrosis (control vs. remote IPC: 45±3% vs. 41±3%, p=n.s.).Finally, in Mb-deficient mice (Mb-/-) remote IPC caused an increase in NO species, but was without effects on infarct size (control vs. remote IPC: 31±1% vs. 35±2% p=n.s.).All values are means±SEM. Conclusion:A concerted action between vascular and myocardial signaling pathways is involved in the NO triggered protection from remote ischemic preconditioning.While eNOS is essentially required for the formation of circulation NO species as triggering mechanisms, Mb in the heart is required for the activation of nitrite to nitric oxide leading to protection of the myocardium at risk.

Diagnosis of transplant rejection requires tissue biopsy and entails risks. Here, we describe a new 19F MRI approach for noninvasive visualization of organ rejection via the macrophage host response. For this, we employed biochemically inert emulsified perfluorocarbons (PFCs), known to be preferentially phagocytized by monocytes and macrophages. Isografts from C57BL/6 or allografts from C57B10.A mice were heterotopically transplanted into C57BL/6 recipients. PFCs were applied intravenously followed by 1H/19F MRI at 9.4 T 24 h after injection. 1H images showed a similar position and anatomy of the graft in the abdomen for both cases. However, corresponding 19F signals were only observed in allogenic tissue. 1H/19F MRI enabled us to detect the initial immune response not later than 3 days after surgery, when conventional parameters did not reveal any signs of rejection. In allografts, the observed 19F signal strongly increased with time and correlated with the extent of rejection. In separate experiments, rapamycin was used to demonstrate the ability of 19F MRI to monitor immunosuppressive therapy. Thus, PFCs can serve as positive contrast agent for the early detection of transplant rejection by 19F MRI with high spatial resolution and an excellent degree of specificity due to lack of any 19F background.

The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of 123I- and 99mTc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake.