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Systemic atherosclerotic inflammation following acute myocardial infarction

Nikhil JoshiBy Nikhil Joshi (Edinburgh, United Kingdom)
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Dr NV Joshi, Dr I Toor, Dr AS Shah, Professor EJR Van Beek, Dr A Fletcher, Dr NL Mills, Dr JHF Rudd, Professor KAA Fox, Dr MR Dweck, Professor DE Newby


Purpose of the study
In murine models, acute myocardial infarction causes atherosclerotic inflammation and progression. Using combined positron emission and computed tomography (PET-CT), we investigated whether this phenomenon occurs in humans.  We determined whether aortic atherosclerotic plaque inflammation demonstrated by 18F-FDG uptake would be increased in patients with a recent myocardial infarction in comparison to patients with stable coronary heart disease, and whether this would be most marked in those with larger infarctions. Furthermore, we explored whether infarct size could predict recurrent early myocardial infarction.
Forty patients with recent myocardial infarction and 40 with stable angina pectoris underwent thoracic 18F-fluorodeoxyglucose (18F-FDG) and 18F-fluoride PET-CT. Radiotracer uptake was measured in aortic atheroma and non-vascular tissue (para-spinal muscle). In 1,003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary atherothombotic events.   
Compared to patients with stable angina, patients with myocardial infarction had increased aortic 18F-FDG uptake (mean TBRmax 2.15±0.30 versus 1.84±0.18, P<0.0001) despite having similar aortic atherosclerotic burden (aortic Agatston score: 135[0-805] versus 538[4-1870] AU, P=0.12; coronary artery calcium score: stable angina 599 [60-1302] versus myocardial infarction 159 [42-456] AU, P=0.006) and para-spinal muscular 18F-FDG uptake (0.79±0.25 versus 0.75±0.21, P=0.52). Patients with ST-segment elevation myocardial infarction had larger infarcts (peak plasma troponin concentration 32,300[10,200->50,000] versus 3,800[1,000-9,200] ng/L, P<0.0001) and greater aortic 18F-FDG uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST elevation myocardial infarction. Aortic 18F-FDG uptake correlated with peak plasma troponin concentration (r=0.42, P=0.01) in all patients with myocardial infarction. There were no differences in aortic 18F-fluoride uptake within the patient groups. On multivariate analysis, peak troponin I concentrations were an independent predictor of early recurrent myocardial infarction (tertile-3 versus tertile-1: relative risk 4.30 [95%CI, 1.85-9.96], p=0.001) but did not predict late re-infarction.
Using 18F-FDG PET imaging, we have demonstrated increased metabolic activity in remote atherosclerotic plaques in patients with recent myocardial infarction. This uptake exceeded that observed in patients with stable coronary disease, who had a greater coronary atherosclerotic burden, and correlated with the degree of myocardial necrosis suggesting a causal association. Using the GRACE registry, we explored the validity of our findings from the imaging cohort to assess whether infarct size and the associated increase in atherosclerotic inflammation could predict recurrent coronary atherothombotic events in every day clinical practice. Patients with the largest infarcts had more than a four-fold increase in their risk of early recurrent myocardial infarction with baseline tertiles of plasma troponin concentration emerging as an independent predictor of these events. We therefore provide clinical data to support the hypothesis that myocardial infarction exacerbates systemic atherosclerotic inflammation, destabilizes remote atheromatous plaque and causes an increase in recurrent atherothrombotic events.
Figure from abstract by Nikhil Joshi

Increased anti-fibrinolytic proteins characterize elderly individuals with un-healthy ageing due to cardiovascular disease and cognitive decline

Judit CubedoBy Judit Cubedo (Barcelona, Spain)


Judit Cubedo 1,2 *, Teresa Padróa, 2 *, Francesc Formiga 3, Assumpta Ferrer 4, Glòria Padrós 5, Lina Badimon 1,2,6

(1) Cardiovascular Research Center (CSIC-ICCC); (2) Biomedical Research Institute Sant Pau (IIB-Sant Pau); (3) Internal Medicine Service, University Hospital of Bellvitge; (4) Primary Healthcare Centre El Plà CAP-I, Sant Feliu de Llobregat; (5) Clinical Laboratoy L'Hospitalet-Cornellà; (6) Cardiovascular Research Chair UAB; Barcelona, Spain.
*Equal contribution


Ageing is one of the most important risk factors for cardiovascular disease (CVD) progression and clinical event presentation. Moreover, CVD is an important contributor to cognitive decline in older people. We sought to identify proteins potentially involved in healthy longevity by investigating the plasma proteome in a group of healthy-ageing octogenarians in comparison with an age-matched group of patients with un-healthy-ageing and atherothrombotic disease.
Plasma samples were obtained from octogenarian subjects (870years). Healthy-ageing octogenarians (preserved functional and cognitive state) without any previous clinical manifestation of CVD (HA-NoCVD; N=38), and un-healthy-ageing patients with cognitive (MEC<25) and functional (Barthel<90) decline and a previous ischemic event (acute myocardial infarction and/or stroke;UHA-CVD; N=27) were investigated. After depletion of the 7 most abundant proteins the plasma proteome was analyzed by 2D-electrophoresis and mass-spectrometry (MALDI-TOF/TOF).
Coagulation and haemostasis-related proteins represented 39% of the observed changes between healthy and un-healthy ageing patients. Alpha-2-antiplasmin and coagulation-factor-XIII-B-chain were increased in the UHA-CVD group compared to HA-NoCVD (P0.01). These results were validated by ELISA in HA-NoCVD, in UHA-CVD and in an intermediate population without cognitive impairment but with a previous CVD clinical manifestation (HA-CVD; N=35). Protein-AMBP was also increased in UHA-CVD along with changes in the distribution profiles of RBP4 and inter-alpha-trypsin-inhibitor-heavy-chain-H4. Functionally, plasma of UHA-CVD-individuals formed denser fibrin clots and had a decreased fibrinolytic potential compared with plasma of HA-NoCVD-subjects (P0.05).   
Healthy older octogenarians show a coordinated decrease in anti-fibrinolytic proteins, such as alpha-2-antiplasmin and coagulation-factor-XIII, resulting in a softer clot formation and increased spontaneous fibrinolysis and hence an improved capability for microthrombus resolution (Figure 1). Reduction in spontaneous fibrinolytic potential leads to a higher tendency for CVD, cognitive impairment and un-healthy ageing.


Human validation of genes associated with a murine atherosclerotic phenotype

Gerard Pasterkamp, FESCBy Gerard Pasterkamp, FESC (Utrecht, Netherlands)
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Von willebrand factor as a sensor of blood flow: Towards a real time biological assessment of aortic valve interventions

Professor Eric Van Belle, FESCBy Eric Van Belle, FESC (Lille, France)
Eric Van Belle*,1,2 MD,PhD; Antoine Rauch*,2, 3 MD; André Vincentelli,1,2 MD,PhD; Emmanuelle Jeanpierre,2,3PharmD; Paulette Legendre,4; Francis Juthier,1,2 MD,PhD; Carlo Banfi,1,2 MD,PhD; Natacha Rousse, MD1,2; Anne Godier,5 MD,PhD; Claudine Caron,2,3 PharmD; Ahmed Elkalioubie,2, 3 MD,PhD; Delphine Corseaux,2 PhD, Bérénice Marchant; Christophe Zawadzki,2,3, PharmD,PhD; Cédric Delhaye,1 MD; Frédéric Mouquet,1,2MD,PhD; Giulia Chinetti,6 PhD; Bart Staels,6 PhD; Jenny Goudemand,2,3MD,PhD; Brigitte Jude,2,3MD,PhD; Peter J. Lenting,4 PhD; Sophie Susen,2,3 MD,PhD;
1-Department of Cardiology, Lille University Hospital;
2-EA 2693, Lille-II-University;
3-Department of Hematology and Transfusion Lille University Hospital,
4-INSERM U770&UMR_S770, Univ Paris-Sud, Le Kremlin Bicêtre,
5-INSERM UMR 1140, Paris,
6-INSERM UMR 1011, Univ Lille 2, Institut Pasteur de Lille; EGID, France
*The authors contributed equally to the manuscript
Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis(AS). In some circumstances their result can still be inadequate while their evaluation in real-time is challenging. We hypothesized that: 1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor (VWF) defect, could occur within minutes following acute changes in blood flow, 2) a bedside point-of-care assay (PFA-CADP), reflecting HMW-multimers changes, could be used to monitor percutaneous aortic valve procedures.
to investigate the time course of HMW-multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside whole blood assessment.
Methods and results
We investigated the time course of the induction/recovery of HMWmultimers defects under conditions of instantaneous changes in shear stress in an AS-rabbit model. We further investigated the recovery of HMW-multimers and monitored these changes with PFA-CADP in AS-patients undergoing transcatheter aortic valve implantation(TAVI) or balloon valvuloplasty (BAV).
Experiments in the AS-rabbit model demonstrated that induction/recovery of HMWmultimers occurs within 5 minutes. TAVI-patients experienced an acute decrease in shear stress and a recovery of VWF defects within minutes of implantation. In BAV-patients, a modest improvement in shear stress and no recovery of VWF defects were observed. PFACADP profiles mimicked HMW-multimers recovery both in  AVI-patients (correction) and BAV-patients(no correction).
These results demonstrate that variations in VWF multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. Assessing VWF changes overtime with a point-of-care assay like PFA-CADP could be useful to monitor acute changes in blood flow during BAV and TAVI procedures.




Basic and Translational Science Hot Line on Vascular Disease

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.