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The Mitral Annulus (MA) is an anisotropic, fibrous, flexible and dynamical structure. While MA dynamics are well documented, its passive mechanical properties remain poorly investigated to complete the design of adequate prostheses. Mechanical properties in traction on four sections of the MA (aortic, left, posterior and right segments) were assessed using a traction test system with a 30 N load cell and pulling jaws for sample fixation. Samples were submitted to a 1.5 N pre-load, 10 pre-conditioning cycles. Three strain rates were tested (5 %/min, 7 %/min and 13 %/min), the first two up to 10 % strain and the last until rupture. High-resolution diffusion-MRI provided microstructural mapping of fractional anisotropy and mean diffusion within muscle and collagen fibres. Ten MA from porcine hearts were excised resulting in 40 tested samples, out of which 28 were frozen prior to testing. Freezing samples significantly increased Young Moduli for all strain rates. No significant differences were found between Young Moduli at different strain rates (fresh samples 2.4 ± 1.1 MPa, 3.8 ± 2.2 MPa and 3.1 ± 1.8 MPa for increasing strain rates in fresh samples), while significant differences were found when comparing aortic with posterior and posterior with lateral (p 0.012). Aortic segments deformed the most (24.1 ± 9.4 %) while lateral segments endured the highest stress (0.3 MPa), corresponding to higher collagen fraction (0.46) and fractional anisotropy. Passive machinal properties differed between aortic and lateral segments of the MA. The process of freezing samples altered their mechanical properties. Underlying microstructural differences could be linked to changes in strain response.

BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF., METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance P-31 spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice., RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling., CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.

Background Single-voxel proton cardiovascular magnetic resonance spectroscopy (1H-CMRS) benefits from 3 T to detect metabolic abnormalities with the quantification of intramyocardial fatty acids (FA) and creatine (Cr). Conventional point resolved spectroscopy (PRESS) sequence remains the preferred choice for CMRS, despite its chemical shift displacement error (CSDE) at high field (≥ 3 T). Alternative candidate sequences are the semi-adiabatic Localization by Adiabatic SElective Refocusing (sLASER) recommended for brain and musculoskeletal applications and the localized stimulated echo acquisition mode (STEAM). In this study, we aim to compare these three single-voxel 1H-CMRS techniques: PRESS, sLASER and STEAM for reproducible quantification of myocardial FA and Cr at 3 T. Sequences are compared both using breath-hold (BH) and free-breathing (FB) acquisitions. Methods CMRS accuracy and theoretical CSDE were verified on a purposely-designed fat–water phantom. FA and Cr CMRS data quality and reliability were evaluated in the interventricular septum of 10 healthy subjects, comparing repeated BH and free-breathing with retrospective gating. Results Measured FA/W ratio deviated from expected phantom ratio due to CSDE with all sequences. sLASER supplied the lowest bias (10%, vs -28% and 27% for PRESS and STEAM). In vivo, PRESS provided the highest signal-to-noise ratio (SNR) in FB scans (27.5 for Cr and 103.2 for FA). Nevertheless, a linear regression analysis between the two BH showed a better correlation between myocardial Cr content measured with sLASER compared to PRESS (r = 0.46; p = 0.03 vs. r = 0.35; p = 0.07) and similar slopes of regression lines for FA measurements (r = 0.94; p Conclusion When quantifying myocardial lipids and creatine with CMR proton spectroscopy at 3 T, PRESS provided higher SNR, while sLASER was more reproducible both with single BH and FB scans.

The heart has the highest energy demands per gram of any organ in the body and energy metabolism fuels normal contractile function. Metabolic inflexibility and impairment of myocardial energetics occur with several common cardiac diseases, including ischemia and heart failure. This review explores several decades of innovation in cardiac magnetic resonance spectroscopy modalities and their use to noninvasively identify and quantify metabolic derangements in the normal, failing, and diseased heart. The implications of this noninvasive modality for predicting significant clinical outcomes and guiding future investigation and therapies to improve patient care are discussed.

Rationale: Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B (Sdhb-/-). Methods: Two groups of Sdhb-/- tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2′ -deoxy-2′-[18F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology. Results: PET-CT-UUI enabled to detect a rapid growth of Sdhb-/- tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib. Conclusion: These results demonstrate an adaptive resistance of Sdhb-/- tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable in vivo early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors.

The prevalence of heart failure with a preserved ejection fraction (HFpEF) is increasing, but therapeutic options are limited. Oxidative stress is suggested to play an important role in the pathophysiology of HFpEF. However, whether oxidative stress is a bystander due to comorbidities or causative in itself remains unknown. Recent results have shown that depletion of 5-oxoprolinase (OPLAH) leads to 5-oxoproline accumulation, which is an important mediator of oxidative stress in the heart. We hypothesize that oxidative stress induced by elevated levels of 5-oxoproline leads to the onset of a murine HFpEF-like phenotype.Oplah full body knock-out (KO) mice had higher 5-oxoproline levels coupled to increased oxidative stress. Compared with wild-type (WT) littermates, KO mice had increased cardiac and renal fibrosis with concurrent elevated left ventricular (LV) filling pressures, impaired LV relaxation, yet a normal LV ejection fraction. Following the induction of cardiac ischaemia/reperfusion (IR) injury, 52.4% of the KO mice died compared with only 15.4% of the WT mice (P 0.03). Furthermore, KO mice showed a significantly increased atrial, ventricular, kidney, and liver weights compared with WT mice (P 0.05 for all). Cardiac and renal fibrosis were more pronounced following cardiac IR injury in the KO mice and these mice developed proteinuria post-IR injury. To further address the link between 5-oxoproline and HFpEF, 5-oxoproline was measured in the plasma of HFpEF patients. Compared with healthy controls (3.8 ± 0.6 µM), 5-oxoproline levels were significantly elevated in HFpEF patients (6.8 ± 1.9 µM, P 0.0001). Furthermore, levels of 5-oxoproline were independently associated with more concentric remodelling on echocardiography.Oxidative stress induced by 5-oxoproline results in a murine phenotype reminiscent of the clinical manifestation of HFpEF without the need for surgical or pharmacological interference. Better understanding of the role of oxidative stress in HFpEF may potentially lead to novel therapeutic options.

International audience; Positron emission tomography–computed tomography (PET–CT) is the most sensitive molecular imaging modality, but it does not easily allow for rapid temporal acquisition. Ultrafast ultrasound imaging (UUI)—a recently introduced technology based on ultrasonic holography—leverages frame rates of up to several thousand images per second to quantitatively map, at high resolution, haemodynamic, biomechanical, electrophysiological and structural parameters. Here, we describe a pre-clinical scanner that registers PET–CT and UUI volumes acquired simultaneously and offers multiple combinations for imaging. We demonstrate that PET–CT–UUI allows for simultaneous images of the vasculature and metabolism during tumour growth in mice and rats, as well as for synchronized multi-modal cardiac cine-loops. Combined anatomical, functional and molecular imaging with PET–CT–UUI represents a high-performance and clinically translatable technology for biomedical research.

International audience

The impairment of cardiac function following interruption of coronary flow is the consequence of metabolic collapse in the territory affected by myocardial ischemia. Metabolic alterations are also causative for cardiac impairment in diabetes and drug-induced cardiotoxicity. There is a real need to combine as much as possible available information for a better understanding of cardiac diseases. Imaging plays a central role in the exploration of cardiac function and, increasingly, of cardiac vascularization. However, although it has extensive applications in oncology and neurology, imaging of glucose metabolism using positron emission tomography (PET) and 2-deoxy-2[18F]-fluoro-D-glucose (FDG) is seldom used in cardiology. One reason is that glucose is not the major fuel of the heart — it accounts for roughly 30% of the energy source in a resting heart. In addition, cardiac metabolism varies widely according to physiological conditions (prandial status, exercise…) with a tight, complex, and not yet fully understood, regulation. We hypothesized that metabolic imaging of the heart would be a useful source of information for experimental pathophysiology studies, in particular to explore the link between vascularization and tissue metabolism. We developed multimodal imaging approaches in laboratory animals to address this issue in two experimental paradigms. In the first paradigm, we studied the causes and consequences of cardiotoxicity induced by antiangiogenic anticancer treatment. The effects of the administration of sunitinib, a tyrosine kinase inhibitor, were explored from a diagnostic and therapeutic perspective using non-invasive in vivo imaging of mouse heart. We showed that sunitinib induces a metabolic deregulation that was detectable by FDG-PET and correlated these results with an exploration of the underlying mechanisms using proteomics. We found that sunitinib forces the myocardium into anaerobic metabolism and that this early side effect is detected by higher FDG uptake. We also unveiled a previously undescribed delayed side effect of sunitinib, the switch towards an insulin resistance profile in the myocardium. Echocardiography demonstrated that metabolic deregulation is associated with the deterioration of cardiac function and proteomics indicated that this association is likely to be causative. Interestingly, we showed that the co-administration of an endothelin receptor antagonist, completely reversed the cardiotoxic effects of sunitinib, a result with possible clinical implications. In a second paradigm, we attempted to integrate multimodal imaging of the heart beyond its actual limitations and developed a new, original, bimodal imaging instrument combining PET and ultrafast ultrasound imaging (UUI). We showed that cardiac PET/UUI is feasible and allows a perfect co-registration of myocardial FDG and UUI anatomy across the cardiac cycle. Moreover, our system has the potential to visualize intramyocardial capillaries and to detect the deficit in perfusion induced by interruption of coronary flow. PET/UUI provides a co-registration of FDG uptake and increased myocardial stiffness that follows myocardial infarction. This allows discrimination of the nonviable myocardium (no FDG uptake and increased myocardial stiffness) from the impaired but viable myocardium (FDG uptake + increased myocardial stiffness).Our results demonstrate the utility of multiparametric imaging for the study of cardiovascular diseases. The exploration of cardiac glucose metabolism using PET in addition to functional imaging is useful to better understand the mechanisms of antiangiogenic cardiotoxicity. We also demonstrated the feasibility of non-invasive PET/UUI imaging, allows simultaneous mutiparametric imaging. PET/UUI will permit a better understanding of the interaction between metabolism, perfusion, elasticity and function in cardiovascular diseases., Parmi les causes les plus fréquentes de l’atteinte de la fonction cardiaque, on trouve l’interruption du flux sanguin dans une coronaire, conduisant à l’hypoxie et à la diminution des apports nutritifs dans le territoire ischémique, et l’altération du métabolisme cardiaque lié à une pathologie systémique ou à un effet iatrogène. Dans les deux cas il existe un lien étroit entre la vascularisation et le métabolisme cardiaque, c’est pourquoi l’exploration combinée de ces deux paramètres serait une source d’information importante pour mieux comprendre les mécanismes pathophysiologiques sous-jacents. Actuellement, l’imagerie médicale est utilisée larga manu pour suivre l’anatomie, la fonction et la vascularisation du cœur, mais l’imagerie métabolique reste peu utilisée en cardiologie. L’une des raisons vient du fait que l’imagerie métabolique repose essentiellement sur la tomographie par émission de positons (TEP) au 2-désoxy-2[18F]-fluoro-D-glucose (FDG), alors que le glucose n’est pas le substrat principal du myocarde (environ 30% du métabolisme au repos).Partant de l’hypothèse que l’imagerie du métabolisme glucidique cardiaque était importante pour explorer le lien entre vascularisation et métabolisme cardiaque, nous avons développé une approche d’imagerie multimodale préclinique appliquée à deux paradigmes.Dans un premier paradigme, nous avons exploré les effets cardiotoxiques d’un médicament anti-angiogénique. Les effets de l’administration du sunitinib, un inhibiteur des récepteurs à activité tyrosine kinase, ont été étudiés d’un point de vue diagnostique et thérapeutique par l’imagerie cardiaque chez la souris. Nous avons démontré que le sunitinib induit d’abord une adaptation du métabolisme cardiaque, détectable en TEP par une augmentation de la captation du FDG, puis est suivie d’une diminution du flux métabolique. La corrélation des résultats d’imagerie avec des analyses protéomiques a montré que le myocarde passe d’un métabolisme aérobie à un métabolisme anaérobie puis devient progressivement insulino-résistant. La carence en substrats énergétiques pourrait expliquer que le cœur développe une dysfonction diastolique observable par échocardiographie. Sur un plan pratique nous avons montré que l’administration d’un antagoniste des récepteurs à l’endothéline supprime les effets cardiotoxiques du sunitinib chez la souris, suggérant une utilité potentielle comme traitement adjuvant en clinique.Dans un second paradigme, nous avons exploré l’infarctus du myocarde grâce à un nouveau système d’imagerie préclinique hybride développé dans notre laboratoire, qui combine la TEP et l’imagerie ultrasonore ultrarapide (IUU). Nous avons tout d’abord réalisé l’acquisition multiparamétrique simultanée de la captation du FDG, de la perfusion myocardique grâce au Doppler ultrasensible, et de la dureté tissulaire grâce à l’imagerie par ondes de cisaillements. La TEP/IUU nous a permis de mieux différencier les zones viables et non-viables après ischémie aigue du myocarde. La zone infarcie présentait une absence de perfusion, une diminution de la captation du FDG et une augmentation de la dureté tissulaire due au remodelage cicatriciel. Dans la zone bordante l’infarctus, la captation du FDG préservée et l’augmentation de la dureté tissulaire ont été interprétées comme liées à une dysfonction diastolique.Ce travail de thèse démontre l’intérêt de l’imagerie multimodale pour des applications cardiovasculaires. L’utilisation de l’imagerie métabolique en combinaison avec l’imagerie de la fonction cardiaque nous a permis de mieux comprendre les mécanismes cardiotoxiques du sunitinib. La conception et la validation de notre système original d’imagerie multiparamétrique TEP/IUU permet de réaliser des acquisitions simultanées pour étudier le lien entre la vascularisation, le métabolisme, la dureté tissulaire et la fonction cardiaque.

The impairment of cardiac function following interruption of coronary flow is the consequence of metabolic collapse in the territory affected by myocardial ischemia. Metabolic alterations are also causative for cardiac impairment in diabetes and drug-induced cardiotoxicity. There is a real need to combine as much as possible available information for a better understanding of cardiac diseases. Imaging plays a central role in the exploration of cardiac function and, increasingly, of cardiac vascularization. However, although it has extensive applications in oncology and neurology, imaging of glucose metabolism using positron emission tomography (PET) and 2-deoxy-2[18F]-fluoro-D-glucose (FDG) is seldom used in cardiology. One reason is that glucose is not the major fuel of the heart — it accounts for roughly 30% of the energy source in a resting heart. In addition, cardiac metabolism varies widely according to physiological conditions (prandial status, exercise…) with a tight, complex, and not yet fully understood, regulation. We hypothesized that metabolic imaging of the heart would be a useful source of information for experimental pathophysiology studies, in particular to explore the link between vascularization and tissue metabolism. We developed multimodal imaging approaches in laboratory animals to address this issue in two experimental paradigms. In the first paradigm, we studied the causes and consequences of cardiotoxicity induced by antiangiogenic anticancer treatment. The effects of the administration of sunitinib, a tyrosine kinase inhibitor, were explored from a diagnostic and therapeutic perspective using non-invasive in vivo imaging of mouse heart. We showed that sunitinib induces a metabolic deregulation that was detectable by FDG-PET and correlated these results with an exploration of the underlying mechanisms using proteomics. We found that sunitinib forces the myocardium into anaerobic metabolism and that this early side effect is detected by higher FDG uptake. We also unveiled a previously undescribed delayed side effect of sunitinib, the switch towards an insulin resistance profile in the myocardium. Echocardiography demonstrated that metabolic deregulation is associated with the deterioration of cardiac function and proteomics indicated that this association is likely to be causative. Interestingly, we showed that the co-administration of an endothelin receptor antagonist, completely reversed the cardiotoxic effects of sunitinib, a result with possible clinical implications. In a second paradigm, we attempted to integrate multimodal imaging of the heart beyond its actual limitations and developed a new, original, bimodal imaging instrument combining PET and ultrafast ultrasound imaging (UUI). We showed that cardiac PET/UUI is feasible and allows a perfect co-registration of myocardial FDG and UUI anatomy across the cardiac cycle. Moreover, our system has the potential to visualize intramyocardial capillaries and to detect the deficit in perfusion induced by interruption of coronary flow. PET/UUI provides a co-registration of FDG uptake and increased myocardial stiffness that follows myocardial infarction. This allows discrimination of the nonviable myocardium (no FDG uptake and increased myocardial stiffness) from the impaired but viable myocardium (FDG uptake + increased myocardial stiffness).Our results demonstrate the utility of multiparametric imaging for the study of cardiovascular diseases. The exploration of cardiac glucose metabolism using PET in addition to functional imaging is useful to better understand the mechanisms of antiangiogenic cardiotoxicity. We also demonstrated the feasibility of non-invasive PET/UUI imaging, allows simultaneous mutiparametric imaging. PET/UUI will permit a better understanding of the interaction between metabolism, perfusion, elasticity and function in cardiovascular diseases.; Parmi les causes les plus fréquentes de l’atteinte de la fonction cardiaque, on trouve l’interruption du flux sanguin dans une coronaire, conduisant à l’hypoxie et à la diminution des apports nutritifs dans le territoire ischémique, et l’altération du métabolisme cardiaque lié à une pathologie systémique ou à un effet iatrogène. Dans les deux cas il existe un lien étroit entre la vascularisation et le métabolisme cardiaque, c’est pourquoi l’exploration combinée de ces deux paramètres serait une source d’information importante pour mieux comprendre les mécanismes pathophysiologiques sous-jacents. Actuellement, l’imagerie médicale est utilisée larga manu pour suivre l’anatomie, la fonction et la vascularisation du cœur, mais l’imagerie métabolique reste peu utilisée en cardiologie. L’une des raisons vient du fait que l’imagerie métabolique repose essentiellement sur la tomographie par émission de positons (TEP) au 2-désoxy-2[18F]-fluoro-D-glucose (FDG), alors que le glucose n’est pas le substrat principal du myocarde (environ 30% du métabolisme au repos).Partant de l’hypothèse que l’imagerie du métabolisme glucidique cardiaque était importante pour explorer le lien entre vascularisation et métabolisme cardiaque, nous avons développé une approche d’imagerie multimodale préclinique appliquée à deux paradigmes.Dans un premier paradigme, nous avons exploré les effets cardiotoxiques d’un médicament anti-angiogénique. Les effets de l’administration du sunitinib, un inhibiteur des récepteurs à activité tyrosine kinase, ont été étudiés d’un point de vue diagnostique et thérapeutique par l’imagerie cardiaque chez la souris. Nous avons démontré que le sunitinib induit d’abord une adaptation du métabolisme cardiaque, détectable en TEP par une augmentation de la captation du FDG, puis est suivie d’une diminution du flux métabolique. La corrélation des résultats d’imagerie avec des analyses protéomiques a montré que le myocarde passe d’un métabolisme aérobie à un métabolisme anaérobie puis devient progressivement insulino-résistant. La carence en substrats énergétiques pourrait expliquer que le cœur développe une dysfonction diastolique observable par échocardiographie. Sur un plan pratique nous avons montré que l’administration d’un antagoniste des récepteurs à l’endothéline supprime les effets cardiotoxiques du sunitinib chez la souris, suggérant une utilité potentielle comme traitement adjuvant en clinique.Dans un second paradigme, nous avons exploré l’infarctus du myocarde grâce à un nouveau système d’imagerie préclinique hybride développé dans notre laboratoire, qui combine la TEP et l’imagerie ultrasonore ultrarapide (IUU). Nous avons tout d’abord réalisé l’acquisition multiparamétrique simultanée de la captation du FDG, de la perfusion myocardique grâce au Doppler ultrasensible, et de la dureté tissulaire grâce à l’imagerie par ondes de cisaillements. La TEP/IUU nous a permis de mieux différencier les zones viables et non-viables après ischémie aigue du myocarde. La zone infarcie présentait une absence de perfusion, une diminution de la captation du FDG et une augmentation de la dureté tissulaire due au remodelage cicatriciel. Dans la zone bordante l’infarctus, la captation du FDG préservée et l’augmentation de la dureté tissulaire ont été interprétées comme liées à une dysfonction diastolique.Ce travail de thèse démontre l’intérêt de l’imagerie multimodale pour des applications cardiovasculaires. L’utilisation de l’imagerie métabolique en combinaison avec l’imagerie de la fonction cardiaque nous a permis de mieux comprendre les mécanismes cardiotoxiques du sunitinib. La conception et la validation de notre système original d’imagerie multiparamétrique TEP/IUU permet de réaliser des acquisitions simultanées pour étudier le lien entre la vascularisation, le métabolisme, la dureté tissulaire et la fonction cardiaque.

OBJECTIVES: Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model. Identification of reliable approaches to evaluate cardiac grafts is key in the development of protocols for heart transplantation with DCDD. METHODS: Hearts isolated from anaesthetized male Wistar rats (n = 34) were exposed to various perfusion protocols. To simulate DCDD conditions, rats were exsanguinated and maintained at 37°C for 15-25 min (warm ischaemia). Isolated hearts were perfused with modified Krebs-Henseleit buffer for 10 min (unloaded), arrested with cardioplegia, stored for 3 h at 4°C and then reperfused for 120 min (unloaded for 60 min, then loaded for 60 min). Left ventricular (LV) function was assessed using an intraventricular micro-tip pressure catheter. Statistical significance was determined using the non-parametric Spearman rho correlation analysis. RESULTS: After 120 min of reperfusion, recovery of LV work measured as developed pressure (DP)-heart rate (HR) product ranged from 0 to 15 ± 6.1 mmHg beats min(-1) 10(-3) following warm ischaemia of 15-25 min. Several haemodynamic parameters measured during early, unloaded perfusion at the time of heart procurement, including HR and the peak systolic pressure-HR product, correlated significantly with contractile recovery after cardioplegic storage and 120 min of reperfusion (P < 0.001). Coronary flow, oxygen consumption and lactate dehydrogenase release also correlated significantly with contractile recovery following cardioplegic storage and 120 min of reperfusion (P < 0.05). CONCLUSIONS: Haemodynamic and biochemical parameters measured at the time of organ procurement could serve as predictive indicators of contractile recovery. We believe that evaluation of graft suitability is feasible prior to transplantation with DCDD, and may, consequently, increase donor heart availability.

We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron emission tomography (PET) for molecular imaging, x-ray computed tomography (CT) for anatomical imaging, co-registration and attenuation correction, and ultrafast ultrasound imaging (UUI) for motion-correction, hemodynamic and biomechanical imaging. In order to ensure a precise co-registration of simultaneous PET-UUI acquisitions, ultrasound probes attached to an ultrafast ultrasound scanner are operated in the field of view (FOV) of a small animal PET/CT scanner using a remote-controlled micro-positioner. Here we explore the effect of the presence of ultrasound probes on PET image quality. We compare the performance of PET and image quality with and without the presence of probes in the PET field of view, both in vitro following the NEMA-NU-4-2008 standard protocol, and in vivo in small animals. Overall, deviations in the quality of images acquired with and without the ultrasound probes were under 10% and under 7% for the NEMA protocol and in vivo tests, respectively. Our results demonstrate the capability of the PETRUS device to acquire multimodal images in vivo without significant degradation of image quality.

Gebiet: Chirurgie Biomedizintechnik Biophysik Transplantationsmedizin Kardiologie Abstract: OBJECTIVES: – Oxygenation of blood and other physiological solutions are routinely required in fundamental research for both in vitro and in vivo experimentation. However, very few oxygenators with suitable priming volumes (

OBJECTIVES The number of heart transplantations is limited by donor organ availability. Donation after circulatory determination of death (DCDD) could significantly improve graft availability; however, organs undergo warm ischaemia followed by reperfusion, leading to tissue damage. Laboratory studies suggest that mechanical postconditioning [(MPC); brief, intermittent periods of ischaemia at the onset of reperfusion] can limit reperfusion injury; however, clinical translation has been disappointing. We hypothesized that MPC-induced cardioprotection depends on fatty acid levels at reperfusion. METHODS Experiments were performed with an isolated rat heart model of DCDD. Hearts of male Wistar rats (n = 42) underwent working-mode perfusion for 20 min (baseline), 27 min of global ischaemia and 60 min reperfusion with or without MPC (two cycles of 30 s reperfusion/30 s ischaemia) in the presence or absence of high fat [(HF); 1.2 mM palmitate]. Haemodynamic parameters, necrosis factors and oxygen consumption (O2C) were assessed. Recovery rate was calculated as the value at 60 min reperfusion expressed as a percentage of the mean baseline value. The Kruskal-Wallis test was used to provide an overview of differences between experimental groups, and pairwise comparisons were performed to compare specific time points of interest for parameters with significant overall results. RESULTS Percent recovery of left ventricular (LV) work [developed pressure (DP)-heart rate product] at 60 min reperfusion was higher in hearts reperfused without fat versus with fat (58 ± 8 vs 23 ± 26%, P < 0.01) in the absence of MPC. In the absence of fat, MPC did not affect post-ischaemic haemodynamic recovery. Among the hearts reperfused with HF, two significantly different subgroups emerged according to recovery of LV work: low recovery (LoR) and high recovery (HiR) subgroups. At 60 min reperfusion, recovery was increased with MPC versus no MPC for LV work (79 ± 6 vs 55 ± 7, respectively; P < 0.05) in HiR subgroups and for DP (40 ± 27 vs 4 ± 2%), dP/dtmax (37 ± 24 vs 5 ± 3%) and dP/dtmin (33 ± 21 vs 5 ± 4%; P < 0.01 for all) in LoR subgroups. CONCLUSIONS Effects of MPC depend on energy substrate availability; MPC increased recovery of LV work in the presence, but not in the absence, of HF. Controlled reperfusion may be useful for therapeutic strategies aimed at improving post-ischaemic recovery of cardiac DCDD grafts, and ultimately in increasing donor heart availability.

International audience; The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system. Here, we explored the cardiotoxicity of the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective. We showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis and reduced left ventricular ejection fraction as demonstrated by echocardiography. The capacity of positron emission tomography with [ 18 F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-administration of the endothelin receptor antagonist, macitentan, to sunitinib-treated animals prevented both metabolic defects, restored glucose uptake and cardiac function, and prevented myocardial fibrosis. These results support the endothelin system in mediating the cardiotoxic effects of sunitinib and endothelin receptor antagonism as a potential therapeutic approach to prevent cardiotoxicity. Furthermore, metabolic and functional imaging can monitor the cardiotoxic effects and the benefits of endothelin antagonism in a theranostic approach.