Acute phase determinant of post-thrombotic syndrome: A review of the literature.

BACKGROUND: Post-thrombotic syndrome (PTS) is the main long-term complication of deep vein thrombosis (DVT). Several therapies are being evaluated to prevent or to treat PTS. Identifying the patients most likely to benefit from these therapies presents a significant challenge. OBJECTIVES: The objective of this review was to identify risk factors for PTS during the acute phase of DVT. ELIGIBILITY CRITERIA: We searched the PubMed and Cochrane databases for studies published between January 2000 and January 2021, including randomized clinical trials, meta-analyses, systematic reviews and observational studies. RESULTS: Risk factors for PTS such as proximal location of DVT, obesity, chronic venous disease, history of DVT are associated with higher risk of PTS. On the initial ultrasound-Doppler, a high thrombotic burden appears to be a predictor of PTS. Among the evaluated biomarkers, some inflammatory markers such as ICAM-1, MMP-1 and MMP-8 appear to be associated with a higher risk of developing PTS. Coagulation disorders are not associated with risk of developing PTS. Role of endothelial biomarkers in predicting PTS has been poorly explored. Lastly, vitamin K antagonist was associated with a higher risk of developing PTS when compared to direct oral anticoagulants and low molecular weight heparin. CONCLUSIONS: Several risk factors during the acute phase of VTE are associated with an increased risk of developing PTS. There is a high-unmet medical need to identify potential biomarkers for early detection of patients at risk of developing PTS after VTE. Inflammatory and endothelial biomarkers should be explored in larger prospective studies to identify populations that could benefit from new therapies.

Perioperative management of venous recanalization in a patient with inherited antithrombin deficiency: case report.

Background: Inherited antithrombin (AT) deficiency (ATD) is a severe thrombophilia causing venous thromboembolism, which can be complicated by postthrombotic syndrome (PTS). Venous recanalization, used to treat PTS, often requires a temporary withdrawal of anticoagulant therapy. In ATD patients, there is a risk of insufficient perioperative anticoagulation due to altered heparin response. Key Clinical Question: There is no consensus on how to manage perioperative anticoagulation in ATD patients. Clinical Approach: Warfarin-unfractionated heparin transition could be a more reliable strategy than low-molecular-weight heparin transition because unfractionated heparin anti-Xa activity not only reflects heparin-bound AT but also AT's activity, which correlates strongly with therapeutic anticoagulation. Biological monitoring could thus decrease the number of plasma-derived AT supplementation. Conclusion: This study describes a successful perioperative management of anticoagulation for venous recanalization that could be suggested to type 1 ATD patients with PTS.

Vasa vasorum interna in the carotid wall of active forms of Takayasu arteritis evidenced by ultrasound localization microscopy.

Introduction: Takayasu arteritis (TA) is associated with microvascularization of the wall of large arteries and is related to inflammation. Ultrasound localization microscopy (ULM), combining ultrafast ultrasound imaging with microbubble (MB) injection, can track the path of MBs within the arterial wall and thus provide imaging of the vasa vasorum. From the analysis of MB tracks in the common carotid arteries of patients with active TA, we report the presence of microvessels in connection with the carotid lumen (i.e., vasa vasorum interna [VVI]). Methods: ULM maps were obtained on five patients with active disease in the observational single-center series of the TAK-UF study. MB tracks connected to the carotid lumen were automatically identified, allowing the reconstruction of VVI. Results: MB tracking allows us to observe a microvascular network on the inner part of the wall, with some vessels in communication with the carotid lumen. This type of vessel was identified in all patients with active TA (n = 5) with a median of 2.2 [1.1-3.0] vessels per acquisition (2D longitudinal view of 3 cm of the common carotid artery). The blood flow within these vessels is mainly centrifugal; that is, toward the adventitia (88% [54-100] of MB tracks with flow directed to the outer part of the wall). Conclusion: VVI are present in humans in the case of active TA and emphasize the involvement of the intima in the pathological process. ClinicalTrials.gov Identifier: NCT03956394.

Four-dimensional flow cardiovascular magnetic resonance aortic cross-sectional pressure changes and their associations with flow patterns in health and ascending thoracic aortic aneurysm.

BACKGROUND: Ascending thoracic aortic aneurysm (ATAA) is a silent and threatening dilation of the ascending aorta (AscAo). Maximal aortic diameter which is currently used for ATAA patients management and surgery planning has been shown to inadequately characterize risk of dissection in a large proportion of patients. Our aim was to propose a comprehensive quantitative evaluation of aortic morphology and pressure-flow-wall associations from four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) data in healthy aging and in patients with ATAA. METHODS: We studied 17 ATAA patients (64.7 ± 14.3 years, 5 females) along with 17 age- and sex-matched healthy controls (59.7 ± 13.3 years, 5 females) and 13 younger healthy subjects (33.5 ± 11.1 years, 4 females). All subjects underwent a CMR exam, including 4D flow and three-dimensional anatomical images of the aorta. This latter dataset was used for aortic morphology measurements, including AscAo maximal diameter (iDMAX) and volume, indexed to body surface area. 4D flow MRI data were used to estimate 1) cross-sectional local AscAo spatial (∆PS) and temporal (∆PT) pressure changes as well as the distance (∆DPS) and time duration (∆TPT) between local pressure peaks, 2) AscAo maximal wall shear stress (WSSMAX) at peak systole, and 3) AscAo flow vorticity amplitude (VMAX), duration (VFWHM), and eccentricity (VECC). RESULTS: Consistency of flow and pressure indices was demonstrated through their significant associations with AscAo iDMAX (WSSMAX:r = -0.49, p < 0.001; VECC:r = -0.29, p = 0.045; VFWHM:r = 0.48, p < 0.001; ∆DPS:r = 0.37, p = 0.010; ∆TPT:r = -0.52, p < 0.001) and indexed volume (WSSMAX:r = -0.63, VECC:r = -0.51, VFWHM:r = 0.53, ∆DPS:r = 0.54, ∆TPT:r = -0.63, p < 0.001 for all). Intra-AscAo cross-sectional pressure difference, ∆PS, was significantly and positively associated with both VMAX (r = 0.55, p = 0.002) and WSSMAX (r = 0.59, p < 0.001) in the 30 healthy subjects (48.3 ± 18.0 years). Associations remained significant after adjustment for iDMAX, age, and systolic blood pressure. Superimposition of ATAA patients to normal aging trends between ∆PS and WSSMAX as well as VMAX allowed identifying patients with substantially high pressure differences concomitant with AscAo dilation. CONCLUSION: Local variations in pressures within ascending aortic cross-sections derived from 4D flow MRI were associated with flow changes, as quantified by vorticity, and with stress exerted by blood on the aortic wall, as quantified by wall shear stress. Such flow-wall and pressure interactions might help for the identification of at-risk patients.

Symptomatic Upper Extremity Peripheral Artery Disease is Associated With Poor Outcomes and a Broad Spectrum of Etiologies.

The symptomatic upper extremity peripheral artery disease (sUE-PAD) is poorly studied compared with the lower extremity peripheral artery disease (LE-PAD). We aimed to describe sUE-PAD etiologies and outcomes at 2 years. From an observational survey conducted in two French tertiary hospitals, demographic characteristics, etiology, treatment, and outcomes during follow-up were collected on patients with ICD-10 I74.2 code (arterial thrombosis of the upper limbs). We identified 181 patients (53% male, 55 ± 17 years) with hypothenar hammer syndrome (13.8%), cardioembolism (13.3%), atheroma (12.7%), or connective tissue disease (10.5%). No etiology could be found for 16.0% of them. The amputation rate was 13.3%, and lasting symptoms remained at 21.3%. During follow-up, atrial fibrillation occurred in 1 patient and cancer in 4. At 2 years, 59 patients were lost to follow-up, 110 patients were alive, and 12 patients had died. Age and cancer were associated with death. sUE-PAD is not benign, with 20% impaired upper extremity outcome and 10% overall mortality at 2 years. Less frequent than LE-PAD, sUE-PAD presents different characteristics: more women, younger age, and a broad spectrum of etiologies. sUE-PAD requires thorough etiological assessment and is considered to be associated with a severe overall prognosis.

Treatment of severe symptomatic aortic valve stenosis using non-invasive ultrasound therapy: a cohort study.

BACKGROUND: Calcific aortic stenosis is commonly treated using surgical or transcatheter aortic valve replacement; however, many patients are not considered suitable candidates for these interventions due to severe comorbidities and limited life expectancy. As such, non-invasive therapies might offer alternative therapeutic possibilities in these patients. This study aimed to assess the safety of non-invasive ultrasound therapy and its ability to improve valvular function by softening calcified valve tissue. METHODS: This prospective, multicentre, single-arm series enrolled 40 adult patients with severe symptomatic aortic valve stenosis at three hospitals in France, the Netherlands, and Serbia between March 13, 2019, and May 8, 2022. Patients were treated with transthoracically delivered non-invasive ultrasound therapy. Follow-ups were scheduled at 1, 3, 6, 12, and 24 months. The primary endpoints were procedure-related deaths within 30 days and improved valve function. We report the 6-month data. This study is registered at ClinicalTrials.gov, NCT03779620 and NCT04665596. FINDINGS: 40 high-risk patients with a mean Society of Thoracic Surgeons score of 5·6% (SD 4·4) and multiple severe comorbidities were included. The primary endpoint, procedure-related mortality, did not occur; furthermore, no life-threatening or cerebrovascular events were reported. Improved valve function was confirmed up to 6 months, reflected by a 10% increase in mean aortic valve area from 0·58 cm2 (SD 0·19) at baseline to 0·64 cm2 (0·21) at follow-up (p=0·0088), and a 7% decrease in mean pressure gradient from 41·9 mm Hg (20·1) to 38·8 mm Hg (17·8; p=0·024). At 6 months, the New York Heart Association score had improved or stabilised in 24 (96%) of 25 patients, and the mean Kansas City Cardiomyopathy Questionnaire score had improved by 33%, from 48·5 (SD 22·6) to 64·5 (21·0). One serious procedure-related adverse event occurred in a patient who presented with a transient decrease in peripheral oxygen saturation. Non-serious adverse events included pain, discomfort during treatment, and transient arrhythmias. INTERPRETATION: This novel, non-invasive ultrasound therapy for calcified aortic stenosis proved to be safe and feasible. FUNDING: Cardiawave.

Fluoroquinolone Use Preceding Visceral Artery Dissection: A Case Series.

Fluoroquinolones (FQ), commonly prescribed antibiotics, may trigger aortic and carotid dissections. We report three successive cases of visceral artery dissection: one patient with celiac trunk dissection and two with dissection of the superior mesenteric artery. These events occurred up to 4 months after 7 to 14 days of FQ treatment (2 cases of ofloxacin, 1 of norfloxacin). There was no other apparent cause of dissection. These dissections were isolated, apart from a minimal aortic dissection separate from the visceral arterial dissection in one case. A case series cannot certify the relationship between dissection and FQ, but it can be hypothesized. The association between fluoroquinolone use and higher occurrence of aneurysm and dissection remains discussed in aortic syndrome. The potential link between FQ and visceral artery dissection is even less described but should be reported in the absence of previous cases in the literature. The pathophysiological theory is the induction of overexpression of some matrix metalloproteinases and a decrease of their inhibitors, provoking a dysregulation in collagen synthesis and degradation of the extracellular matrix.

The fundamental mechanisms of the Korotkoff sounds generation.

Blood pressure measurement is the most widely performed clinical exam to predict mortality risk. The gold standard for its noninvasive assessment is the auscultatory method, which relies on listening to the so-called "Korotkoff sounds" in a stethoscope placed at the outlet of a pneumatic arm cuff. However, more than a century after their discovery, the origin of these sounds is still debated, which implies a number of clinical limitations. We imaged the Korotkoff sound generation in vivo at thousands of images per second using ultrafast ultrasound. We showed with both experience and theory that Korotkoff sounds are paradoxically not sound waves emerging from the brachial artery but rather shear vibrations conveyed in surrounding tissues by the nonlinear pulse wave propagation. When these shear vibrations reached the stethoscope, they were synchronous, correlated, and comparable in intensity with the Korotkoff sounds. Understanding this mechanism could ultimately improve blood pressure measurement and provide additional understanding of arterial mechanical properties.

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Is carotid web an arterial wall dysplasia? A histological series.

INTRODUCTION: Described for 60 years under various names, the carotid web is a suspected cause of cryptogenic stroke, especially in young patients. The web creates an intraluminal protrusion that may contribute to turbulent flow and thrombus embolization into cerebral arteries. Although the carotid web has frequently been related to arterial fibrodysplasia, its natural history and pathological description remain unclear. PATIENTS: Among all consecutive patients admitted to the stroke unit of Sainte-Anne Hospital and referred to the vascular surgery department from January 2015 to December 2022, we retrospectively identified 9 patients with a carotid web. The surgical specimens of the 9 patients were submitted to systematic pathological analysis. RESULTS: The patients with a histologically confirmed carotid web were young (median age was 42 years), prominently women (7/9), and presenting with low cardiovascular risk. Eight patients had a stroke proven by a magnetic resonance imaging, and 1 had transient monocular amaurosis. The typical pathological lesion supporting the imaging pattern of the carotid web was a focal eccentric intimal hyperplasia forming a protruding lesion characterized by a population of vascular smooth muscle cells intermingled in an abundant, most often loose extracellular matrix. Pathologically proven thrombus was observed in 4 cases. Importantly atherosclerosis was absent. CONCLUSION: Histological features in our 9 cases strengthen carotid web characterization as a homogeneous pattern of localized intimal hyperplasia. It is a unique entity consistent with intimal fibroplasia, distinct from medial fibromuscular dysplasia and early atherosclerosis.

Role of the advanced nurse practitioner within the vascular team: A qualitative study of vascular physicians and nurses.

Objective: To assess the perception of Advanced Nurse Practitioners (ANP) by physicians and nurses in vascular medicine. As the status of ANP in France was recently enacted by law in 2018, we aimed to investigate physicians and nurses working with patients suffering from Peripheral Artery Disease (PAD) to gather their opinions and draw the cooperation outlines these practitioners could have with an ANP. Methods: A qualitative study based on in-depth interviews was conducted among healthcare practitioners taking care of patients with PAD: 10 physicians working either in a private practice settings or hospital settings or both, and eight nurses working within a hospital inpatients vascular unit. Verbatim responses were extracted and coded according to a continuous thematization method. Results: Three main features emerged from participants' responses. Vascular medicine has a specific organization with a significant lack of time and staff to fulfill the mission regarding patients' severity of illness. Second, the ANP is wanted to fill part of this gap. The expected benefits include a smoother care pathway and increased capacity for cardiovascular education and prevention, especially during consultations. Lastly, some clarification is required to integrate such new practitioners within vascular teams already in place. Conclusion: Advanced nurse practitioners could be the missing link in a "Vascular team" by creating a continuum in the care of patients with PAD, ensuring clinical assessment, nursing supervision, adverse event screening, and renewing drug prescriptions with the required adaptations while ensuring essential part of therapeutic education adapted to each patient.

Assessment of Takayasu's arteritis activity by ultrasound localization microscopy.

BACKGROUND: Ultrasound localization microscopy (ULM) based on ultrafast ultrasound imaging of circulating microbubbles (MB) can image microvascular blood flows in vivo up to the micron scale. Takayasu arteritis (TA) has an increased vascularisation of the thickened arterial wall when active. We aimed to perform vasa vasorum ULM of the carotid wall and demonstrate that ULM can provide imaging markers to assess the TA activity. METHODS: Patients with TA were consecutively included with assessment of activity by the National Institute of Health criteria: 5 had active TA (median age 35.8 [24.5-46.0] years) and 11 had quiescent TA (37.2 [31.7-47.3] years). ULM was performed using a 6.4 MHz probe and a dedicated imaging sequence (plane waves with 8 angles, frame rate 500 Hz), coupled with the intravenous injection of MB. Individual MB were localised at a subwavelength scale then tracked, allowing the reconstruction of the vasa vasorum flow anatomy and velocity. FINDINGS: ULM allowed to show microvessels and to measure their flow velocity within the arterial wall. The number of MB detected per second in the wall was 121 [80-146] in active cases vs. 10 [6-15] in quiescent cases (p = 0.0005), with a mean velocity of 40.5 [39.0-42.9] mm.s-1 in active cases. INTERPRETATION: ULM allows visualisation of microvessels within the thickened carotid wall in TA, with significantly greater MB density in active cases. ULM provides a precise visualisation in vivo of the vasa vasorum and gives access to the arterial wall vascularisation quantification. FUNDING: French Society of Cardiology. ART (Technological Research Accelerator) biomedical ultrasound program of INSERM, France.

Methods: Aortic wall deformation assessment by ultrafast ultrasound imaging: Application to bicuspid aortic valve associated aortopathy.

Purpose: Aortic maximal rate of systolic distention (MRSD) is a prognosis factor of ascending aorta dilatation with magnetic resonance imaging. Its calculation requires precise continuous tracking of the aortic diameter over the cardiac cycle, which is not feasible by focused ultrasound. We aimed to develop an automatic aortic acquisition using ultrafast ultrasound imaging (UUI) to provide access to the aortic MRSD. Methods: A phased array probe and developed sequences at 2000 frames/s were used. A created interface automatically tracked the anterior and posterior aortic walls over the cardiac cycle. Tissue Doppler allowed a precise estimation of the walls' movements. MRSD was the maximum derivative of the aortic diameter curve over time. To assess its feasibility, 34 patients with bicuspid aortic valve (BAV) and 31 controls were consecutively included to evaluate the BAV-associated aortopathy at the sinus of Valsalva, the tubular ascending aorta, and the aortic arch. Results: UUI acquisitions and the dedicated interface allow tracking of the aortic diameter and calculating the MRSD for the BAV patients and controls (mean age of 34 vs. 43 years, p = 0.120). A trend toward lower deformation in the different aortic segments was observed, as expected. Still, only the MRSD with UUI was significantly different at the sinus of Valsalva in this small series: (0.61 .103.s-1 [0.37-0.72] for BAV patients vs. 0.92 .103.s-1 [0.72-1.02] for controls, p = 0.025). Conclusion: Aortic deformation evaluated with UUI deserves attention with a simple and automated measurement technique that could assess the segmental aortic injury associated with BAV.

Occurrence of Major Local Lower Limb Events in Type 2 Diabetic Patients with Lower Extremity Arterial Disease: Impact of Metformin.

BACKGROUNDS: Patients with type 2 diabetes mellitus (T2DM) are particularly at risk of developing major adverse cardiovascular events (MACE) and peripheral artery disease (PAD) due to an acceleration of the atherosclerotic process linked to hyperglycemia and inflammation with a greater risk of local complications. We aimed to identify the predictive factors for major adverse limb events (MALE) in T2DM patients with PAD to manage modifiable factors at an early stage. METHODS: This is a prospective study in which T2DM patients with PAD were included from November 2017 to May 2018 and followed over 12 months. The predictive factors for the onset of MALE, MACE, and death from all causes have been identified. RESULTS: A total of 100 patients were included; 37% of the patients developed a MALE. After multivariate analysis, metformin was associated with a decrease of MALE (odds ratio (OR) = 0.26; 95% confidence interval (CI) [0.10; 0.68]; P = 0.007), and a history of the treatment of intravenous iloprost was associated with an increased risk of MALE (OR = 5.70; 95% CI [1.31; 31.93]; P = 0.029). Regular physical activity was associated with a decreased risk of MACE (OR = 0.07; 95% CI [0; 0.44]; P = 0.021). A history of stroke and a history of venous thromboembolism were associated with an increased all-cause mortality risk with OR = 3.68; 95% CI [1.17; 11.5]; P = 0.025 and OR = 3.78; 95% CI [1.16; 12.3]; P = 0.027. CONCLUSIONS: Metformin is protective against local complications in people with diabetes with PAD and should be prescribed to diabetic patients with PAD at an early stage.

Association of Lipoprotein(a) Levels With Incidence of Major Adverse Limb Events.

Importance: High lipoprotein(a) (Lp[a]) levels are involved in the development of cardiovascular events, particularly in myocardial infarction, stroke, and peripheral artery disease. Studies assessing the Lp(a) levels associated with adverse lower-limb events are lacking. Objective: To assess the association between Lp(a) levels and incidence of major adverse limb events in unselected hospitalized patients. Design, Setting, and Participants: This large retrospective monocentric cohort study was conducted from January 1, 2000, to December 31, 2020. Data were derived from the clinical information system of the Hôpital Européen Georges-Pompidou, a Paris-based university hospital. Patients who underwent at least 1 Lp(a) measurement at the center during the study period were included. Patients who had no follow-up data or who had the first Lp(a) measurement after the study outcome had occurred were excluded. Data analyses were performed from May 2021 to January 2022. Main Outcomes and Measures: The primary outcome was the first inpatient major adverse limb event, defined as a major amputation, peripheral endovascular revascularization, or peripheral surgical revascularization, during follow-up. Secondary outcomes included individual components of the primary outcome. Lipoprotein(a) levels were categorized as follows: normal (<50 mg/dL), high (50 to <134 mg/dL), and very high (≥134 mg/dL); to convert Lp(a) values to milligrams per liter, multiply by 0.1. Results: A total of 16 513 patients (median [IQR] age, 58.2 [49.0-66.7] years; 9774 men [59.2%]) were included in the cohort. The median (IQR) Lp(a) level was 24 (10.0-60.0) mg/dL. The 1-year incidence of major adverse limb event was 2.44% in the overall population and 4.54% among patients with very high Lp(a) levels. High (adjusted accelerated failure time [AFT] exponential estimate: 0.43; 95% CI, 0.24-0.78; Benjamini-Hochberg-corrected P = .01) and very high (adjusted AFT exponential estimate: 0.17; 95% CI, 0.07-0.40; Benjamini-Hochberg-corrected P < .001) Lp(a) levels were independently associated with an increased risk of major adverse limb event. Conclusions and Relevance: Results of this study showed that higher Lp(a) levels were independently associated with an increased risk of a major adverse limb event in hospitalized patients. The Lp(a) measurement needs to be taken into account to improve lower-limb vascular risk assessment.

[French Chronic Myeloid Leukemia Intergroup 2022 recommendations for managing the risk of cardiovascular events on ponatinib in chronic myeloid leukemia]. / Recommandations 2022 du groupe Fi-LMC pour la gestion du risque d'événements cardiovasculaires sous ponatinib dans la leucémie myéloïde chronique.

Tyrosine kinase inhibitors targeting the BCR-ABL1 oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 3rd generation tyrosine kinase inhibitor ponatinib is licensed for the treatment of chronic, accelerated or blast phase chronic myeloid leukaemia patients who are resistant to dasatinib or nilotinib; intolerant of dasatinib or nilotinib and for whom further treatment with imatinib is not clinically appropriate; or who express the T315I mutation. Ponatinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of ponatinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in ponatinib-treated patients.

Left ventricular diastolic early and late filling quantified from 4D flow magnetic resonance imaging.

PURPOSE: The purpose of this study was to investigate the value of 4D flow MRI for mitral filling measurements, using transthoracic echocardiography (TTE) and 2D flow MRI as references, as well as identify relationships with age and left ventricle (LV) remodeling in healthy volunteers. MATERIAL AND METHODS: Fifty healthy volunteers (22 men, 28 women; mean age, 51.3 ± 16.9 [SD] years; age range: 20-80 years) prospectively underwent TTE and MRI on the same day. 4D flow volume acquisition was done at 3T with reconstructed spatial/temporal resolutions: 1 × 1.48 × 2.38 mm3/34 ms. Early (E) and late (A) flow rate and maximal velocity peaks were measured from 4D flow data with three strategies: static planes at 1) the mitral valve leaflets tip (4DLT) and 2) annulus (4Dann); and 3) while tracking the annulus through time (4Dtrack). RESULTS: 4DLT- and 4Dtrack-derived E/A ratios were in good agreement with 2D flow and TTE estimates with a superiority over maximal velocities (4DLT: r = 0.71 and r = 0.66; 4Dtrack: r = 0.74 and r = 0.71, respectively) of flow rates (4DLT: r = 0.89 and 0.72; 4Dtrack: r = 0.91 and 0.76, respectively). Measurements of 4DLT and 4Dtrack were highly reproducible (ICC = 0.89 and 0.95, respectively) and significantly correlated with age and LV remodeling (4DLT: r = -0.76 and ρ = -0.49; 4Dtrack: r = -0.79 and ρ = -0.51, respectively). CONCLUSION: E/A ratio can be accurately measured using 4D flow MRI either at a fixed mitral leaflet tip location or through annulus plane time-resolved tracking.