Tristan Mirault

Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia

Despite a well-recognized clinical benefit of the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with imatinib-resistant/-intolerant or newly diagnosed chronic myeloid leukemia, recent evidence suggests that nilotinib has a propensity to increase the risk of occlusive arterial events, especially in patients with pre-existing cardiovascular risk factors. Given the key role of lipids in cardiovascular diseases, we studied the plasma lipid profile and global cardiovascular risk prior to and during nilotinib therapy in a series of 27 patients in the setting of a prospective single center study. Data from a minimum 1-year follow up showed that nilotinib significantly increased total, low- and high-density lipoprotein cholesterol within three months. Consequently, the proportion of patients with non-optimal low-density lipoprotein cholesterol increased from 48.1% to 88.9% by 12 months, leading to cholesterol-lowering drug intervention in 22.2% of patients. The proportion of patients with low levels of high-density lipoprotein cholesterol decreased from 40.7% to 7.4% by 12 months. In contrast, a significant decrease in triglycerides was observed. Global cardiovascular risk worsened in 11.1% of patients due to diabetes or occlusive arterial events. Whether hypercholesterolemia was the main driver of occlusive arterial events was uncertain: a longer follow up is necessary to ask whether nilotinib-induced hypercholesterolemia increases long-term risk of atherosclerotic diseases. Nevertheless, given key atherogenic properties of low-density lipoprotein cholesterol, we conclude that when prescribing nilotinib, commitment to detect lipid disorders at baseline and during follow up is mandatory given their frequency, requirement for changes in lifestyle or drug intervention, and potential for long-term cardiovascular complications.

Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischaemia: evidence of vasculogenic potential

Very small embryonic-like stem cells (VSELs) are multipotent stem cells localised in adult bone marrow (BM) that may be mobilised into peripheral blood (PB) in response to tissue injury. We aimed to quantify VSELs in BM and PB of patients with critical limb ischaemia (CLI) and to test their angiogenic potential in vitro as well as their therapeutic capacity in mouse model of CLI. We isolated BM VSELs from patients with CLI and studied their potential to differentiate into vascular lineages. Flow and imaging cytometry showed that VSEL counts were lower in BM (p< 0.001) and higher (p< 0.001) in PB from CLI patients compared to healthy controls, suggesting that ischaemia may trigger VSELs mobilisation in this patient population. Sorted BM-VSELs cultured in angiogenic media acquired a mesenchymal phenotype (CD90+, Thy-1 gene positive expression). VSEL-derived cells had a pattern of secretion similar to that of endothelial progenitor cells, as they released low levels of VEGF-A and inflammatory cytokines. Noteworthy, VSELs triggered post-ischaemic revascularisation in immunodeficient mice (p< 0.05 vs PBS treatment), and acquired an endothelial phenotype either in vitro when cultured in the presence of VEGF-B (Cdh-5 gene positive expression), or in vivo in Matrigel implants (human CD31+ staining in neo-vessels from plug sections). In conclusion, VSELs are a potential new source of therapeutic cells that may give rise to cells of the endothelial lineage in humans.

Non-invasive assessment of liver fibrosis by transient elastography in post transfusional iron overload

Background:  Liver fibrosis, assessed by biopsy, is the main complication of post transfusional liver iron overload. Transient elastography (TE) is a new, non invasive method able to measure liver stiffness (LS) caused by fibrosis.

Rapid onset of peripheral artery disease in a chronic myeloid leukemia patient without prior arterial disorder: direct relationship with nilotinib exposure and clinical outcome

The second‐generation tyrosine kinase inhibitor (TKI) of the BCR‐ABL1 oncoprotein nilotinib used in patients with chronic myeloid leukemia is suspected to increase the risk of arterial occlusion, especially in patients with pre‐existing cardiovascular risk factors or established cardiovascular diseases. Here, we describe a case of unexpected and rapid onset of symptomatic peripheral artery disease (PAD) associated with silent stenosis of digestive and renal arteries in a nilotinib‐treated patient devoid of significant cardiovascular diseases (CVD) risk factor, prior atherosclerotic disease, or other cause of arterial damage. This is the first report to establish a direct relationship between nilotinib exposure and PAD and to reveal that arterial damage is irreversible despite rapid drug withdrawal. However, functional outcome was favorable upon rapid TKI replacement, specific cardiovascular disease management, and development of collateral arterial network.

Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders

Lowe syndrome (LS) is a rare X‐linked disorder caused by mutations in the oculocerebrorenal gene (OCRL), encoding OCRL, a phosphatidylinositol 5–phosphatase with a RhoGAP domain. An abnormal rate of haemorrhagic events was found in a retrospective clinical survey. Herein, we report the results of exploration of haemostasis in six LS patients. All patients had normal coagulation tests but prolonged closure times (CTs) in the PFA–100 system. Healthy donors’ blood samples incubated with a RhoA kinase inhibitor had prolonged CTs. This suggests that an aberrant RhoA pathway in platelets contributes to CT prolongation and primary haemostasis disorders in LS.

Arterial Stiffening with Ultrafast Ultrasound Imaging Gives New Insight into Arterial Phenotype of Vascular Ehlers-Danlos Mouse Models

OBJECTIVE  Vascular Ehlers-Danlos syndrome (vEDS) is associated with arterial ruptures due to a mutant gene encoding collagen type III (Col-III). To better understand the role of Col-III, we aimed at evaluating aortic stiffness and dynamic stiffening in vEDS mouse models, with either a quantitative (col3KO mice) or a qualitative Col-III defect (col3KI mice). MATERIALS AND METHODS  Abdominal aortic wall pulse wave velocities (PWV) in col3KO and col3KI mice were compared to their respective wild type (WT) littermates using a 15 MHz ultrafast ultrasonic transducer. A carotid catheter continuously monitored pressure changes due to phenylephrine injections. PWV1, generated at diastolic blood pressure (DBP), and PWV2, at systolic blood pressure (SBP) were recorded. Difference between PWV2 and PWV1 (Delta-PWV) normalized by the pulse pressure (PP), corresponding to the aortic stiffening over the cardiac cycle, were compared between mutant and WT mice, as well as the regression slope of PWV as a function of pressure. RESULTS  Delta-PWV/PP was lower in col3KO (p = 0.033) and col3KI mice (p < 0.001) vs. WT-mice regardless of the pressure level. The slope of PWV1 with DBP increase showed a lower arterial stiffness in mutant mice vs. controls in both models. This difference was amplified when evaluating stiffness at systolic blood pressure levels with PWV2. CONCLUSION  In both vEDS mouse models, aortic stiffening was reduced, mainly driven by a lower stiffness at systolic blood pressure. Defective Col-III may be responsible for this, as it is utilized when pressure rises. These pre-clinical data could explain vascular fragility observed in vEDS patients.

Evaluation of a new non-invasive ultrasonic device for venous recanalization: Assessment of feasibility and safety of thrombotripsy at 2.25 MHz in an in vitro model of recent venous thrombosis

Persistent occlusion following venous thrombosis is associated with an increased risk of post-thrombotic syndrome. Venous recanalization may prevent this complication. Ultrasonic histotripsy has been shown to fractionate thrombus through a cavitation cloud generated by an external transducer and restore the flow [1]. In this study, we aimed at demonstrating that thrombotrispy can be performed with high accuracy using a 2.25 MHz transducer in vitro in a recent human blood clot.

Insight in vascular fragility induced by collagen structural change using ultrafast ultrasound imaging in a mouse model of vascular Ehlers-Danlos syndrome

Multiple collagen types are critical for proper function of the vascular system, with type III being responsible for imparting strength in the vessel wall. Patients with mutant gene encoding type III collagen experience arterial ruptures, called vascular Ehlers-Danlos syndrome (vEDS). In order to better characterize their arterial mechanical properties, we developed a Knock-In Gly183Arg mice (col3KI-mice) presenting a qualitative default in type III collagen, similar to the human disease. Our goal was to assess the aortic mechanical behaviour by measuring the pulse wave velocity (PWV) at different blood pressure levels.