Mechanical and biological heart valve prostheses are currently used in patients. Despite recent improvements, the ideal prosthesis still does not exist. Prosthesis-related problems necessitate reoperation or cause death in 50-60% of patients within 10 years post-implantation.The risk for prosthetic valve thrombosis can reach 6% per patient-year. In recent years, transcatheter aortic valve implantation (TAVI) has become a valuable and steadily increasing alternative to surgical valve replacement. Recent works indicate that thrombosis also occurs after the TAVI procedure, even if patients are under dual antiplatelet therapy. In a general manner, despite the immense number of materials used in medicine as blood contacting devices, only few fundamental mechanisms of blood/material interactions are elucidated by now.
We hypothesize that TAVI complications relates to the extent of local flow alterations, as well as to patient's chronic low-grade inflammatory status. These conditions may interfere with the resolution of inflammatory responses, thereby promoting thrombosis, microemboli, or calcium phosphate deposits.
The main objectives of our proposal are:
- To study the association of patients' clinical characteristics with TAVI complications, i.e., thrombosis, stroke rate, prosthesis degeneration.
- To assess the utility of imaging modalities, and systemic biomarkers to predict adverse events, and improve outcome.
Before TAVI procedure, brain MRI will be performed and several systemic biomarkers will be collected to assess the thrombotic and inflammation status. After the procedure and at 6 months follow-up a transcranial Doppler, a 4D flow CMR, a 3D CT scan a 3D transesophageal echocardiography will be performed. Systemic biomarkers will be also collected after the procedure and at follow-up
This is a cooperative study between the Department of Cardiology at Sapienza University of Rome and the Department of Cardiology at University of Liège | ulg
Following systemic biomarkers will be assessed:
Thrombotic status
1. Platelet phenotype
- Platelet count, mean platelet volume.
- Surface platelet activation markers (whole blood multicolor automated flow cytometry): phosphatydilserine (Annexin V), P-selectin (CD62P), fibrin(ogen) binding.
- Platelet-neutrophils and platelet-monocytes aggregates (whole blood flow cytometry).
- Reticulated immature platelet fraction, as a marker of inflammation-induced megakarypoiesis, leading to the production of hyper-reactive platelets.
- Soluble platelet activation markers: PF4, sCD40L, sGPVI.
- Platelet reactivity/refractoriness, on-treatment platelet reactivity: aggregometry (ADP, arachidonic acid)
2. VWF
- VWF multimers or VWF-dependent shear stress-induced platelet adhesion/aggregation assay (cone-and-plate viscometer, laminar and pulsatile flow).
- ADAMTS-13 activity (FRETS-VWF73 assay): a disintegrin and metalloproteinase with a thrombospondin motif repeats 13 with antithrombotic properties due to cleavage of VWF in smaller, less active multimers (Low ADAMTS13 activity is associated with the risk of ischemic stroke (Sonneveld et al Blood 2015)).
3. Coagulation/fibrinolysis
- PT, aPTT
- Fibrinogen
- Prothrombin
- Thrombin-antithrombin complexes
- D-dimers
- PAI-1
- Tissue factor-expressing microparticles
Metabolic climate
- Total cholesterol, HDL, LDL, triglycerides
- Adipokines (adiponectin, ghrelin, leptin, visfatin, resistin)
- Glucagon-like peptide-1
- Homocysteine/folate (homocysteine can alter innate immune function by promoting NETs formation and disturbs homeostasis between platelets and neutrophils, Joshi et al Sci Rep 2016)
Inflammation
- C-reactive protein
- Differential white blood cell count ¿ Neutrophil-lymphocyte, platelet-lymphocyte ratios (elevated NLR and PLR are associated with the occurrence of 30-day adverse outcomes, similar to the STS-PROM score, a high variation of NLR from baseline to discharge may help stratify patients that underwent TAVR in addition to traditional risk factors, Condado et al IJC 2106)
- IL-6 (prothrombogenic inflammatory cytokine)
- IL-1/IL-18 (markers of inflammasome activation notably by high LDL-C)
- sST2 (prognostic marker in heart failure and AS)
- Type I procollagen carboxy-and aminoterminal propeptides (PICP, PINP) (markers of ECM degradation)
Neutrophil phenotype
- Proportion of high density and low density neutrophils (neutrophils expressing the ox-LDL receptor, LOX-1, Condamine et al Science Immunology 2016) (low density neutrophils are produced in blood under non-resolving inflammatory conditions, Manz and Boettcher, Nat Rev Immunol 2014)
- Myeloperoxidase activity
- NET markers: DNA/citrullinated histone H3, pentraxin 3, elastase
Brain injury biomarkers
- BNP
- Serum UCH-L1
- S100 calcium binding protein B (S-100B)
- Neuron-specific enolase (NSE)
- Myelin basic protein (MBP)
- Glial fibrillary acidic protein (GFAP).
All these biomarkers will be evaluated at baseline, after TAVI pocedure and at 6 months follow-up
Further, more advanced imaging techniques will be used to assess the prostehtic valve morphology, profile, reology, and impact on dynamic of fluids
Before TAVI procedure, brain MRI will be performed and systemic biomarkers will be collected to assess the thrombotic and inflammation status. After the procedure and at 6 months follow-up a transcranial Doppler, a 4D flow CMR, a 3D CT scan a 3D transesophageal echocardiography will be performed. Systemic biomarkers will be also collected after the procedure and at follow-up
With all these information we expected to better understand the interaction between patients' clinical characteristics and TAVI complications, i.e., thrombosis, stroke rate, prosthesis degeneration and to assess the utility of different imaging modalities, and systemic biomarkers to predict adverse events, and improve outcome.