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Background(335/350) ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking.MethodsSystemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients >18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150-200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 hours, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism.DiscussionSYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy.Trial registrationTrial Registration Number:NCT03539133;Registration Date29.05.2018Administrative informationNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (seehttp://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).Funding {4}This trial was supported by the German Research Foundation SFB 1116 Grant No. 236177352, as well as project grants BO 4264/1-1 (F.B.); the German Diabetes Center (DDZ), which is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the state North Rhine-Westphalia and from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD).Trialsstructured Study Protocol templateTrialsguidance: the numbers in curly brackets (e.g. {5a}) are SPIRIT item identifiers.Please do not remove the numbers in curly brackets, or any heading that contains them.The item identifiers are slightly out of sequence to make the document flow more easily but it is important that they remain in the document to allow electronic searches by SPIRIT item number.https://trialsjournal.biomedcentral.com/submission-guidelines/preparing-your-manuscript/study-protocoll

RationaleThe impact of aortic valve stenosis (AS) on systemic endothelial function independent of standard modifiable risk factors (SMuRFs) is unknown.ObjectiveWe hypothesized that AS induces subclinical hemoglobin release from red blood cells (RBCs) following transvalvular passage due to post-stenotic aberrant blood flow and that cell-free hemoglobin (fHb) may limit endothelial NO bioavailability, affecting vascular function.Methods and ResultsAS induces swirling blood flow in the ascending aorta which impairs RBC integrity with consecutive release of fHb. Indeed, swirl flow magnitude assessed by 4D flow cardiac magnetic resonance correlates with fHb levels. Elevated systemic fHb reduces NO bioavailability and thus impairs endothelial cell function as evidenced by impaired flow mediated dilation (FMD). In addition, we here demonstrate impaired FMD in an experimental model of AS utilising C57BL/6 mice with preserved left ventricular function and without cardiovascular risk factors. In this model, endothelial dysfunction is accompanied by significantly increased fHb, exaggerated NO consumption and increased plasma levels of nitroso species and the final NO oxidation product, nitrate. Scavenging of fHb by infusion of haptoglobin reversed these deleterious effects. There observations were verified by transfer experiments with human plasma (sampled from patients with AS sheduled for TAVR) using a murine aortic ring bioassay system where the plasma from AS patients induced endothelial dysfunction when compared to plasma from control individuals without AS. Importantly, these deleterious effects were reversed by successful aortic valve replacement via TAVR independent of SMuRFs.ConclusionsIn aortic valve stenosis, increases in post-valvular swirl blood flow in the ascending aorta induces subclinical hemolysis that impairs NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement limits NO scavenging by realigning of postvalvular blood flow to normal physiological patterns.

Abdominal aortic aneurysms (AAA) are a common vascular disorder with a high mortality due to the prevalence of aortic ruptures. The underlying pathomechanisms are complex and involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), synthesized at the plasma membrane by three HA synthase isoenzymes (HAS1-3), is not only a major constituent of the ECM but also known to directly affect the phenotype of vascular smooth muscle cells as well as immunological responses. Specifically, the HAS3 isoenzyme has been reported to play a major role in various inflammatory conditions. Therefore, the aim of the present study was to elucidate the role of HAS3-derived HA in the pathogenesis of abdominal aortic aneurysm. To this end, we used a murine model of Angiotensin II (AngII)-induced abdominal aortic aneurysms and dissections (AAAs/AADs) and could demonstrate that genetic depletion ofHas3improves survival inApoe/Has3double deficient (Apoe/Has3-DKO) mice via the reduced occurrence of aortic ruptures. Mechanistically, fewer elastica breaks were observed inApoe/Has3-DKO mice compared toApoe-KO littermates. This was associated with a decreased infiltration of myeloid immune cells into the vessel wall ofHas3-deficient mice while in parallel elevated numbers of circulating leukocytes were detected. RNA seq analysis from aortic tissue pointed towards a disturbed endothelial-myeloid cell communication as a cause for the diminished recruitment of immune cells to the aortic wall. While endothelial cells were unaffected, upregulation of adhesion receptors as well as the HA receptor CD44, known to mediate leukocyte adhesion to the endothelium, was blunted in monocytes fromApoe/Has3-DKO mice in response to AngII treatment. These findings underline the pivotal detrimental role of monocyte’s HAS3-dependent pericellular HA matrix for an exaggerated immune cell recruitment to inflammatory foci giving here rise for an increased incidence of ruptured aortic aneurysms.

Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty.19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. We aimed to non-invasively image monocyte/macrophage infiltration in response to angioplasty in pig carotid arteries using Fluorine-19 magnetic resonance imaging (19F MRI) to assess early inflammatory response to mechanical injury. Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty.19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. In eight minipigs, injury of the right carotid artery was induced by either balloon oversize angioplasty only (BA, n=4) or in combination with endothelial denudation (BA + ECDN, n=4). PFOB-NE was administered intravenously three days after injury followed by1H and19F MRI to assess vascular inflammatory burden at day six. Vascular response to mechanical injury was validated using immunohistology. Angioplasty was successfully induced in all eight pigs. Response to injury was characterized by positive remodeling with predominantly adventitial wall thickening and adventitial infiltration of monocytes/macrophages.19F signal could be detectedin vivoin four pigs following BA + ECDN with a robust signal-to-noise ratio (SNR) of 14.7 ± 4.8.Ex vivoanalysis revealed a linear correlation of19F SNR to local monocyte/macrophage cell density. Minimum detection limit of infiltrated monocytes/macrophages was as about 400 cells/mm2. Therefore,19F MRI enables quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity. This might open an avenue to non-invasively monitor inflammatory response to mechanical injury after angioplasty and thus to identify individuals with distinct patterns of vascular inflammation promoting restenosis.One Sentence Summary19F MRI enables radiation-free quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity.

Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGFß signaling.Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS.MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.