Mechano-electrical interactions and heterogeneities in wild-type and drug-induced long QT syndrome rabbits.

Electromechanical reciprocity - comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) - provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions - such as (drug-induced) acquired long QT syndrome (aLQTS) - might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and IKr -blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations. KEY POINTS: Electromechanical reciprocity comprising excitation-contraction coupling (EMC) and mechano-electric feedback loops (MEC) is essential for physiological cardiac function. Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro-arrhythmic effects. In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) both under physiological conditions (control) and in acquired long QT syndrome (aLQTS). We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and, vice versa, that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control. Our results substantiate the hypothesis that LQTS is an ?electro-mechanical', rather than a 'purely electrical', disease and suggest that acute MEC effects may play an additional role in LQT-related arrhythmogenesis.

A computational model of rabbit geometry and ECG: Optimizing ventricular activation sequence and APD distribution.

Computational modeling of electrophysiological properties of the rabbit heart is a commonly used way to enhance and/or complement findings from classic lab work on single cell or tissue levels. Yet, thus far, there was no possibility to extend the scope to include the resulting body surface potentials as a way of validation or to investigate the effect of certain pathologies. Based on CT imaging, we developed the first openly available computational geometrical model not only of the whole heart but also the complete torso of the rabbit. Additionally, we fabricated a 32-lead ECG-vest to record body surface potential signals of the aforementioned rabbit. Based on the developed geometrical model and the measured signals, we then optimized the activation sequence of the ventricles, recreating the functionality of the Purkinje network, and we investigated different apico-basal and transmural gradients in action potential duration. Optimization of the activation sequence resulted in an average root mean square error between measured and simulated signal of 0.074 mV/ms for all leads. The best-fit T-Wave, compared to measured data (0.038 mV/ms), resulted from incorporating an action potential duration gradient from base to apex with a respective shortening of 20 ms and a transmural gradient with a shortening of 15 ms from endocardium to epicardium. By making our model and measured data openly available, we hope to give other researchers the opportunity to verify their research, as well as to create the possibility to investigate the impact of electrophysiological alterations on body surface signals for translational research.

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.

Analysis of accelerated 4D flow MRI in the murine aorta by radial acquisition and compressed sensing reconstruction.

Preclinical 4D flow MRI remains challenging and is restricted for parallel imaging acceleration due to the limited number of available receive channels. A radial acquisition with combined parallel imaging and temporal compressed sensing reconstruction was implemented to achieve accelerated preclinical 4D flow MRI. In order to increase the accuracy of the measured velocities, a quantitative evaluation of different temporal regularization weights for the compressed sensing reconstruction based on velocity instead of magnitude data is performed. A 3D radial retrospectively triggered phase contrast sequence with a combined parallel imaging and compressed sensing reconstruction with temporal regularization was developed. It was validated in a phantom and in vivo (C57BL/6 J mice), against an established fully sampled Cartesian sequence. Different undersampling factors (USFs [12, 15, 20, 30, 60]) were evaluated, and the effect of undersampling was analyzed in detail for magnitude and velocity data. Temporal regularization weights λ were evaluated for different USFs. Acceleration factors of up to 20 compared with full Nyquist sampling were achieved. The peak flow differences compared with the Cartesian measurement were the following: USF 12, 3.38%; USF 15, 4.68%; USF 20, 0.95%. The combination of 3D radial center-out trajectories and compressed sensing reconstruction is robust against motion and flow artifacts and can significantly reduce measurement time to 30 min at a resolution of 180 µm3 . Concisely, radial acquisition with combined compressed sensing and parallel imaging proved to be an excellent method for analyzing complex flow patterns in mice.

Assessment of diastolic dysfunction: comparison of different cardiovascular magnetic resonance techniques.

AIMS: Heart failure with preserved ejection fraction is still a diagnostic and therapeutic challenge, and accurate non-invasive diagnosis of left ventricular (LV) diastolic dysfunction (DD) remains difficult. The current study aimed at identifying the most informative cardiovascular magnetic resonance (CMR) parameters for the assessment of LVDD. METHODS AND RESULTS: We prospectively included 50 patients and classified them into three groups: with DD (DD+, n = 15), without (DD-, n = 26), and uncertain (DD±, n = 9). Diagnosis of DD was based on echocardiographic E/E', invasive LV end-diastolic pressure, and N-terminal pro-brain natriuretic peptide. CMR was performed at 1.5 T to assess LV and left atrial (LA) morphology, LV diastolic strain rate (SR) by tissue tracking and tagging, myocardial peak velocities by tissue phase mapping, and transmitral inflow profile using phase contrast techniques. Statistics were performed only on definitive DD+ and DD- (total number 41). DD+ showed enlarged LA with LA end-diastolic volume/height performing best to identify DD+ with a cut-off value of ≥0.52 mL/cm (sensitivity = 0.71, specificity = 0.84, and area under the receiver operating characteristic curve = 0.75). DD+ showed significantly reduced radial (inferolateral E peak: DD-: -14.5 ± 6.5%/s vs. DD+: -10.9 ± 5.9%/s, P = 0.04; anterolateral A peak: DD-: -4.2 ± 1.6%/s vs. DD+: -3.1 ± 1.4%/s, P = 0.04) and circumferential (inferolateral A peak: DD-: 3.8 ± 1.2%/s vs. DD+: 2.8 ± 0.8%/s, P = 0.007; anterolateral A peak: DD-: 3.5 ± 1.2%/s vs. DD+: 2.5 ± 0.8%/s, P = 0.048) SR in the basal lateral wall assessed by tissue tracking. In the same segments, DD+ showed lower peak myocardial velocity by tissue phase mapping (inferolateral radial peak: DD-: -3.6 ± 0.7 ms vs. DD+: -2.8 ± 1.0 ms, P = 0.017; anterolateral longitudinal peak: DD-: -5.0 ± 1.8 ms vs. DD+: -3.4 ± 1.4 ms, P = 0.006). Tagging revealed reduced global longitudinal SR in DD+ (DD-: 45.8 ± 12.0%/s vs. DD+: 34.8 ± 9.2%/s, P = 0.022). Global circumferential and radial SR by tissue tracking and tagging, LV morphology, and transmitral flow did not differ between DD+ and DD-. CONCLUSIONS: Left atrial size and regional quantitative myocardial deformation applying CMR identified best patients with DD.

Electro-mechanical (dys-)function in long QT syndrome type 1.

BACKGROUND: Prolonged repolarization is the hallmark of long QT syndrome (LQTS), which is associated with subclinical mechanical dysfunction. We aimed at elucidating mechanical cardiac function in LQTS type 1 (loss of IKs) and its modification upon further prolongation of the action potential (AP) by IKr-blockade (E-4031). METHODS: Transgenic LQT1 and wild type (WT) rabbits (n = 12/10) were subjected to tissue phase mapping MRI, ECG, and epicardial AP recording. Protein and mRNA levels of ion channels and Ca2+ handling proteins (n = 4/4) were determined. In silico single cell AP and tension modeling was performed. RESULTS: At baseline, QT intervals were longer in LQT1 compared to WT rabbits, but baseline systolic and diastolic myocardial peak velocities were similar in LQT1 and WT. E-4031 prolonged QT more pronouncedly in LQT1. Additionally, E-4031 increased systolic and decreased diastolic peak velocities more markedly in LQT1 - unmasking systolic and diastolic LQT1-specific mechanical alterations. E-4031-induced alterations of diastolic peak velocities correlated with the extent of QT prolongation. CONCLUSION: While baseline mechanical function is normal in LQT1 despite a distinct QT prolongation, further prolongation of repolarization by IKr-blocker E-4031 unmasks mechanical differences between LQT1 and WT with enhanced systolic and impaired diastolic function only in LQT1. These data indicate an importance of the extent of QT prolongation and the contribution of different impaired ion currents for conveying mechanical dysfunction.

Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.

AIMS: Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. METHODS AND RESULTS: Transgenic rabbits were generated by oocyte-microinjection of ß-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype. CONCLUSION: Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.

Coronary magnetic resonance imaging after routine implantation of bioresorbable vascular scaffolds allows non-invasive evaluation of vascular patency.

BACKGROUND: Evaluation of recurrent angina after percutaneous coronary interventions is challenging. Since bioresorbable vascular scaffolds (BVS) cause no artefacts in magnetic resonance imaging (MRI) due to their polylactate-based backbone, evaluation of vascular patency by MRI might allow for non-invasive assessment and triage of patients with suspected BVS failure. METHODS: Patients with polylactate-based ABSORB-BVS in proximal coronary segments were examined with 3 Tesla MRI directly (baseline) and one year after implantation. For assessment of coronary patency, a high-resolution 3D spoiled gradient echo pulse sequence with fat-saturation, T2-preparation (TE: 40 ms), respiratory and end-diastolic cardiac gating, and a spatial resolution of (1.08 mm)3 was positioned parallel to the course of the vessel for bright blood imaging. In addition, a 3D navigator-gated T2-weighted variable flip angle turbo spin echo (TSE) sequence with dual-inversion recovery black-blood preparation and elliptical k-space coverage was applied with a voxel size of (1.14 mm)3. For quantitative evaluation lumen diameters of the scaffolded areas were measured in reformatted bright and black blood MR angiography data. RESULTS: 11 patients with implantation of 16 BVS in the proximal coronary segments were included, of which none suffered from major adverse cardiac events during the one year follow up. Vascular patency in all segments implanted with BVS could be reliably assessed by MRI at baseline and after one year, whereas segments with metal stents could not be evaluated due to artefacts. Luminal diameter within the BVS remained constant during the one year period. One patient with atypical angina after BVS implantation was noninvasively evaluated showing a patent vessel, also confirmed by coronary angiography. CONCLUSIONS: Coronary MRI allows contrast-agent free and non-invasive assessment of vascular patency after ABSORB-BVS implantation. This approach might be supportive in the triage and improvement of diagnostic workflows in patients with postinterventional angina and scaffold implantation. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00007456.

Left ventricular regional myocardial motion and twist function in repaired tetralogy of Fallot evaluated by magnetic resonance tissue phase mapping.

OBJECTIVES: We aimed to characterise regional myocardial motion and twist function in the left ventricles (LV) in patients with repaired tetralogy of Fallot (rTOF) and preserved LV global function. METHODS: We recruited 47 rTOF patients and 38 age-matched normal volunteers. Tissue phase mapping (TPM) was performed for evaluating the LV myocardial velocity in longitudinal, radial, and circumferential (Vz, Vr, and VØ) directions in basal, middle, and apical slices. The VØ peak-to-peak (PTP) during systolic phases, the rotation angle of each slice, and VØ inconsistency were computed for evaluating LV twist function and VØ dyssynchrony. RESULTS: As compared to the controls, the rTOF patients presented decreased RV ejection fraction (RVEF) (p = 0.002) and preserved global LV ejection fraction (LVEF). They also demonstrated decreased systolic and diastolic Vz in several LV segments and higher diastolic Vr in the septum (all p < 0.05). A lower VØ PTP, higher VØ inconsistency, and reduced peak net rotation angle (all p < 0.05) were observed. The aforementioned indices demonstrated an altered LV twist function in rTOF patients in an early disease stage. CONCLUSIONS: MR TPM could provide information about early abnormalities of LV regional motion and twist function in rTOF patients with preserved LV global function. KEY POINTS: • Patients with rTOF presented significantly reduced systolic and diastolic Vz in the LV. • rTOF patients demonstrated significantly increased diastolic Vr in the septum. • Abnormal characteristics of the segmental dynamic velocity evolution were shown in rTOF. • rTOF patients presented altered circumferential rotation and velocity inconsistency in early stage.

Segmental biventricular analysis of myocardial function using high temporal and spatial resolution tissue phase mapping.

OBJECTIVE: Myocardial dysfunction of the right ventricle (RV) is an important indicator of RV diseases, e.g. RV infarction or pulmonary hypertension. Tissue phase mapping (TPM) has been widely used to determine function of the left ventricle (LV) by analyzing myocardial velocities. The analysis of RV motion is more complicated due to the different geometry and smaller wall thickness. The aim of this work was to adapt and optimize TPM to the demands of the RV. MATERIALS AND METHODS: TPM measurements were acquired in 25 healthy volunteers using a velocity-encoded phase-contrast sequence and kt-accelerated parallel imaging in combination with optimized navigator strategy and blood saturation. Post processing was extended by a 10-segment RV model and a detailed biventricular analysis of myocardial velocities was performed. RESULTS: High spatio-temporal resolution (1.0 × 1.0 × 6 mm3, 21.3 ms) and the optimized blood saturation enabled good delineation of the RV and its velocities. Global and segmental velocities, as well as time to peak velocities showed significant differences between the LV and RV. Furthermore, complex timing of the RV could be demonstrated by segmental time to peak analysis. CONCLUSION: High spatio-temporal resolution TPM enables a detailed biventricular analysis of myocardial motion and might provide a reliable tool for description and detection of diseases affecting left and right ventricular function.

Preclinical 4D-flow magnetic resonance phase contrast imaging of the murine aortic arch.

PURPOSE: Cardiovascular diseases remain the number one death cause worldwide. Preclinical 4D flow phase contrast magnetic resonance imaging can provide substantial insights in the analysis of aortic pathophysiologies in various animal models. These insights may allow a better understanding of pathophysiologies, therapy monitoring, and can possibly be translated to humans. This study provides a framework to acquire the velocity field within the aortic arch. It analyses important flow values at different locations within the aortic arch. Imaging parameters with high temporal and spatial resolution are provided, that still allow combining this time-consuming method with other necessary imaging-protocols. METHODS: A new setup was established where a prospectively gated 4D phase contrast sequence is combined with a highly sensitive cryogenic coil on a preclinical magnetic resonance scanner. The sequence was redesigned to maintain a close to steady state condition of the longitudinal magnetization and hence to overcome steady state artifacts. Imaging parameters were optimized to provide high spatial and temporal resolution. Pathline visualizations were generated from the acquired velocity data in order to display complex flow patterns. RESULTS: Our setup allows data acquisition with at least two times the rate than that of previous publications based on Cartesian encoding, at an improved image quality. The "steady state" sequence reduces observed artifacts and provides uniform image intensity over the heart cycle. This made possible quantification of blood speed and wall shear stress (WSS) within the aorta and its branches. The highest velocities were observed in the ascending aorta with 137.5 ± 8 cm/s. Peak velocity values in the Brachiocephalic trunk were 57 ± 12 cm/s. Quantification showed that the peak flow occurs around 20 ms post R-wave in the ascending aorta. The highest mean axial wall shear stress was observed in the analysis plane between the left common carotid artery (LCCA) and the left subclavian artery. A stable image quality allows visualizing complex flow patterns by means of streamlines and for the first time, to the best of our knowledge, pathline visualizations from 4D flow MRI in mice. CONCLUSION: The described setup allows analyzing pathophysiologies in mouse models of cardiovascular diseases in the aorta and its branches with better image quality and higher spatial and temporal resolution than previous Cartesian publications. Pathlines provide an advanced analysis of complex flow patterns in the murine aorta. An imaging protocol is provided that offers the possibility to acquire the aortic arch at sufficiently high resolution in less than one hour. This allows the combination of the flow assessment with other multifunctional imaging protocols.

Interregional electro-mechanical heterogeneity in the rabbit myocardium.

BACKGROUND: Increased electrical heterogeneity has been causatively linked to arrhythmic disorders, yet the knowledge about physiological heterogeneity remains incomplete. This study investigates regional electro-mechanical heterogeneities in rabbits, one of the key animal models for arrhythmic disorders. METHODS AND FINDINGS: 7 wild-type rabbits were examined by phase-contrast magnetic resonance imaging in vivo to assess cardiac wall movement velocities. Using a novel data-processing algorithm regional contraction-like profiles were calculated. Contraction started earlier and was longer in left ventricular (LV) apex than base. Patch clamp recordings showed longer action potentials (AP) in LV apex compared to the base of LV, septum, and right ventricle. Western blots of cardiac ion channels and calcium handling proteins showed lower expression of Cav1.2, KvLQT1, Kv1.4, NCX and Phospholamban in LV apex vs. base. A single-cell in silico model integrating the quantitative regional differences in ion channels reproduced a longer contraction and longer AP in apex vs. base. CONCLUSIONS: Apico-basal electro-mechanical heterogeneity is physiologically present in the healthy rabbit heart. An apico-basal electro-mechanical gradient exists with longer APD and contraction duration in the apex and associated regionally heterogeneous expression of five key proteins. This pattern of apical mechanical dominance probably serves to increase pumping efficiency.

Phase-contrast magnet resonance imaging reveals regional, transmural, and base-to-apex dispersion of mechanical dysfunction in patients with long QT syndrome.

BACKGROUND: Regional dispersion of prolonged repolarization is a hallmark of long QT syndrome (LQTS). We have also revealed regional heterogeneities in mechanical dysfunction in transgenic rabbit models of LQTS. OBJECTIVE: In this clinical pilot study, we investigated whether patients with LQTS exhibit dispersion of mechanical/diastolic dysfunction. METHODS: Nine pediatric patients with genotyped LQTS (12.2 ± 3.3 years) and 9 age- and sex-matched healthy controls (10.6 ± 1.5 years) were subjected to phase-contrast magnetic resonance imaging to analyze radial (Vr) and longitudinal (Vz) myocardial velocities during systole and diastole in the left ventricle (LV) base, mid, and apex. Twelve-lead electrocardiograms were recorded to assess the heart rate-corrected QT (QTc) interval. RESULTS: The QTc interval was longer in patients with LQTS than in controls (469.1 ± 39.4 ms vs 417.8 ± 24.4 ms; P < .01). Patients with LQTS demonstrated prolonged radial and longitudinal time-to-diastolic peak velocities (TTP), a marker for prolonged contraction duration, in the LV base, mid, and apex. The longer QTc interval positively correlated with longer time-to-diastolic peak velocities (correlation coefficient 0.63; P < .01). Peak diastolic velocities were reduced in LQTS in the LV mid and apex, indicating impaired diastolic relaxation. In patients with LQTS, regional (TTPmax-min) and transmural (TTPVz-Vr) dispersion of contraction duration was increased in the LV apex (TTPVz_max-min: 38.9 ± 25.5 ms vs 20.2 ± 14.7 ms; P = .07; TTPVz-Vr: -21.7 ± 14.5 ms vs -8.7 ± 11.3 ms; P < .05). The base-to-apex longitudinal relaxation sequence was reversed in patients with LQTS compared with controls (TTPVz_base-apex: 14.4 ± 14.9 ms vs -10.1 ± 12.7 ms; P < .01). CONCLUSION: Patients with LQTS exhibit diastolic dysfunction with reduced diastolic velocities and prolonged contraction duration. Mechanical dispersion is increased in LQTS with an increased regional and transmural dispersion of contraction duration and altered apicobasal longitudinal relaxation sequence. LQTS is an electromechanical disorder, and phase-contrast magnetic resonance imaging Heterogeneity in mechanical dysfunction enables a detailed assessment of mechanical consequences of LQTS.

Myocardial dysfunction in patients with aortic stenosis and hypertensive heart disease assessed by MR tissue phase mapping.

PURPOSE: To identify abnormalities of myocardial velocities in patients with left ventricular pressure overload using magnetic resonance tissue phase mapping (TPM). MATERIAL AND METHODS: Thirty-three patients (nine with hypertensive heart disease [HYP], 24 with aortic stenosis [AS]) and 41 healthy controls were enrolled. To assess left ventricular motion, a basal, midventricular, and apical slice were acquired using three-directional velocity-encoded phase-contrast MR with a 3T system. Target parameters were peak longitudinal (Vz ) and radial (Vr ) velocity in systole and diastole (Peaksys , Peakdias ). Analysis was done on each myocardial segment. In a subgroup (n = 7 HYP, n = 12 AS, n = 24 controls), measurement was repeated during handgrip exercise. RESULTS: AS had significantly lower Vz -Peaksys in the inferolateral and inferoseptal wall (P = 0.003-0.029) and Vr -Peaksys in the septum and anterior wall (P = 0.001-0.013) than controls. Vz -Peakdias and Vr -Peakdias were lower in AS than in controls in almost all segments (P < 0.001-0.028). HYP showed reduced Vz -Peakdias compared to controls in all basal segments as well as in the lateral midventricular wall (P < 0.001-0.045), and reduced Vr -Peakdias compared to controls predominantly in the midventricular and apical segments (P = 0.004-0.042). AS patients with focal fibrosis had significantly reduced myocardial velocities (P = 0.001-0.047) in segments without late enhancement. During exercise, Vz -Peaksys , Vr -Peaksys , and Vz -Peakdias remained unchanged in AS and HYP, but decreased in the lateral wall in controls (P < 0.001-0.043). CONCLUSION: Even with preserved left ventricle (LV) ejection fraction, peak longitudinal and radial velocities of the LV are reduced in AS and HYP, indicating early functional impairment. J. Magn. Reson. Imaging 2016;44:168-177.

In vitro study to simulate the intracardiac magnetohydrodynamic effect.

PURPOSE: Blood flow causes induced voltages via the magnetohydrodynamic (MHD) effect distorting electrograms (EGMs) made during magnetic resonance imaging. To investigate the MHD effect in this context MHD voltages occurring inside the human heart were simulated in an in vitro model system inside a 1.5 T MR system. METHODS: The model was developed to produce MHD signals similar to those produced by intracardiac flow and to acquire them using standard clinical equipment. Additionally, a new approach to estimate MHD distortions on intracardiac electrograms is proposed based on the analytical calculation of the MHD signal from MR phase contrast data. RESULTS: The recorded MHD signals were similar in magnitude to intracardiac signals that would be measured by an electrogram of the left ventricle. The dependency of MHD signals on magnetic field strength and electrode separation was well reflected by an analytical model. MHD signals reconstructed from MR flow data were in excellent agreement with the MHD signal measured by clinical equipment. CONCLUSION: The in vitro model allows investigation of MHD effects on intracardiac electrograms. A phase contrast MR scan was successfully applied to characterize and estimate the MHD distortion on intracardiac signals allowing correction of these effects.

Dual-contrast molecular imaging allows noninvasive characterization of myocardial ischemia/reperfusion injury after coronary vessel occlusion in mice by magnetic resonance imaging.

BACKGROUND: Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y12 (-/-) mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y12 (-/-) mice. CONCLUSIONS: Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury.

Cold ischaemic time and time after transplantation alter segmental myocardial velocities after heart transplantation.

OBJECTIVES: The aim of this study was to investigate changes in segmental, three-directional left ventricular (LV) velocities in patients after heart transplantation (Tx). METHODS: Magnetic resonance tissue phase mapping was used to assess myocardial velocities in patients after Tx (n = 27) with normal LV ejection fraction (63 ± 5%) and those without signs of rejection. Regional wall motion and dyssynchrony were analysed in relation to cold ischaemic time (150 ± 57 min, median = 154 min), age of the donor heart (35 ± 13 years, median = 29 years), time after transplantation (32 ± 26 months, median = 31 months) and global LV morphology and function. RESULTS: Segmental myocardial velocities were significantly altered in patients with cold ischaemic times >155 min resulting in an increase in peak systolic radial velocities (2 of 16 segments, P = 0.03-0.04) and reduced segmental diastolic long-axis velocities (5 of 16 segments, P = 0.01-0.04). Time after transplantation (n = 8 patients <12 months after Tx vs n = 19 >12 months) had a significant influence on systolic radial velocities (increased in 2 of 16 segments, P = 0.01-0.04) and diastolic long-axis velocities (reduced in 5 of 16 segments, P = 0.02-0.04). Correlation analysis and multiple regression revealed significant relationships of cold ischaemic time (R = -0.384, P = 0.048), the donor heart's age (ß= 0.9, P = 0.01) and time from transplantation (ß= -0.36, P = 0.03) with long-axis diastolic dyssynchrony. CONCLUSIONS: Time after transplantation and cold ischaemic time strongly affect segmental systolic and diastolic motion in patients after Tx. The understanding of alterations in regional LV motion in the transplanted heart under stable conditions is essential in order to utilize this methodology in the future as a potentially non-invasive means of diagnosing transplant rejection.

Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits.

BACKGROUND: Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. OBJECTIVE: To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. METHODS: Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. RESULTS: In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. CONCLUSIONS: The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder.

A quantitative comparison of regional myocardial motion in mice, rabbits and humans using in-vivo phase contrast CMR.

BACKGROUND: Genetically manipulated animals like mice or rabbits play an important role in the exploration of human cardiovascular diseases. It is therefore important to identify animal models that closely mimic physiological and pathological human cardiac function. METHODS: In-vivo phase contrast cardiovascular magnetic resonance (CMR) was used to measure regional three-directional left ventricular myocardial motion with high temporal resolution in mice (N=18), rabbits (N=8), and humans (N=20). Radial, long-axis, and rotational myocardial velocities were acquired in left ventricular basal, mid-ventricular, and apical short-axis locations. RESULTS: Regional analysis revealed different patterns of motion: 1) In humans and rabbits, the apex showed slower radial velocities compared to the base. 2) Significant differences within species were seen in the pattern of long-axis motion. Long-axis velocities during systole were fairly homogeneously distributed in mice, whereas humans showed a dominant component in the lateral wall and rabbits in the base. 3) Rotational velocities and twist showed the most distinct patterns in both temporal evolution and relative contribution of base, mid-ventricle and apex, respectively. Interestingly, a marked difference in rotational behavior during early-systole was found in mice, which exhibited clockwise rotation in all slice locations compared to counter-clockwise rotation in rabbits and humans. CONCLUSIONS: Phase contrast CMR revealed subtle, but significantly different regional myocardial motion patterns in mice, rabbits and humans. This finding has to be considered when investigating myocardial motion pattern in small animal models of heart disease.