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.

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.

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.

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.

Diastolic Function Assessment of Left and Right Ventricles by MRI in Systemic Sclerosis Patients.

BACKGROUND: Heart involvement is frequent although often clinically silent in systemic sclerosis (SSc) patients. Early identification of cardiac involvement can be improved by noninvasive methods such as MRI, in addition to transthoracic echocardiography (TTE). PURPOSE: To assess the ability of phase-contrast (PC)-MRI to detect subclinical left (LV) and right (RV) ventricular diastolic dysfunction in SSc patients. STUDY TYPE: Prospective. POPULATION: Thirty-five consecutive SSc patients (49 ± 14 years) and 35 sex- and age-matched healthy controls (48.6 ± 13.5 years) who underwent TTE and MRI in the same week. FIELD STRENGTH/SEQUENCE: 5 T/PC-MRI using a breath-hold velocity-encoded gradient echo sequence. ASSESSMENT: LV TTE (E/E') and LV and RV PC-MRI indices of diastolic function (LV early and late transmitral [EM , EfM , AM , AfM ] and RV transtricuspid [ET , EfT , AT , AfT ] peak filling flow velocities and flow rates, as well as LV [ E M ' ] and RV [ E T ' ] peak longitudinal myocardial velocities during diastole) were measured. STATISTICAL TESTS: Two-tailed t-test, Wilcoxon test, or Fischer test for comparison of variables between SSc and healthy control groups; sensitivity, specificity, receiver-operating-characteristic (ROC) area under the curve (AUC) to assess discriminative ability of variables. A P-value <0.05 was considered statistically significant. RESULTS: TTE LV E/E' and MRI EM / E M ' and ET / E T ' were significantly higher in SSc patients than in controls (8.27 ± 1.25 vs. 6.70 ± 1.66; 9.43 ± 2.7 vs. 6.51 ± 1.50; 6.51 [4.70-10.40] vs. 4.13 [3.22-5.75], respectively) and separated SSc patients and healthy controls with good sensitivity (68%, 71%, and 80%), specificity (85%, 94%, and 62%), and AUC (0.787, 0.807, and 0.765). LV EfM was significantly higher in SSc patients than in controls (347.1 ± 113.7 vs. 284.7 ± 94.6) as RVAfT (277 [231-355] vs. 220 [154-253] mL/sec) with impaired relaxation pattern (EfT /AfT , 0.95 [0.87-1.21] vs. 1.12 [0.93-1.47]). DATA CONCLUSION: MRI was able to detect LV and RV diastolic dysfunction in SSc patients with good accuracy in the absence of LV systolic dysfunction at echocardiography. Use of MRI can allow to better assess the early impact of myocardial fibrosis related to SSc. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Editor's Choice - External Applicability of the COMPASS and VOYAGER-PAD Trials on Patients with Symptomatic Lower Extremity Artery Disease in France: The COPART Registry.

OBJECTIVE: The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world. METHODS: This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models. RESULTS: Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 - 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 - 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 - 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 - 6.9) in the VOYAGER-PAD control arm for major adverse limb events. CONCLUSION: Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials.

Wall Shear Stress Measurement by Ultrafast Vector Flow Imaging for Atherosclerotic Carotid Stenosis.

OBJECTIVE: Carotid plaque vulnerability assessment could guide the decision to perform endarterectomy. Ultrafast ultrasound imaging (UF) can evaluate local flow velocities over an entire 2D image, allowing measurement of the wall shear stress (WSS). We aimed at evaluating the feasibility of WSS measurement in a prospective series of patients with carotid stenosis. METHODS: UF acquisitions, performed with a linear probe, had an effective frame rate of 5000 Hz. The flow velocity was imaged over the entire plaque area. WSS was computed with the vector field speed using the formula: with the blood velocity and µ, the blood viscosity. The WSS measurement method was validated using a calibrated phantom. In vivo, WSS was analyzed in 5 areas of the carotid wall: common carotid artery, plaque ascent, plaque peak, plaque descent, internal carotid artery. RESULTS: Good correlation was found between in vitro measurement and the theoretical WSS values (R2 = 0.95; p < 0.001). 33 patients were prospectively evaluated, with a median carotid stenosis degree of 80 % [75-85]. The maximum WSS value over the cardiac cycle follows the shape of the plaque with an increase during the ascent, reaching its maximum value of 3.25 Pa [2.26-4.38] at the peak of the plaque, and a decrease after passing of the peak (0.93 Pa [0.80-1.19]) lower than the WSS values in the non-stenotic areas (1.47 Pa [1.12-1.77] for the common carotid artery). CONCLUSION: UF allowed local and direct evaluation of the plaque's WSS, thus better characterizing local hemodynamics to identify areas of vulnerability. KEY POINTS: · Ultrafast vector Doppler allows calculation of the wall shear stress (WSS) by measuring velocity vectors over the entire 2D image.. · The setup to measure the WSS has been validated in vitro on a linear flow phantom by comparing measurements to in silico calculations.. · Applying this method to carotid plaque allows us to better describe the hemodynamic constraints that apply along the entire length of the plaque..

Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients.

BACKGROUND: Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis. OBJECTIVES: To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening. METHODS: Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission. RESULTS: Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers. CONCLUSION: Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.

Management of carotid stenosis for primary and secondary prevention of stroke: state-of-the-art 2020: a critical review.

Carotid atherosclerotic plaque is encountered frequently in patients at high cardiovascular risk, especially in the elderly. When plaque reaches 50% of carotid lumen, it induces haemodynamically significant carotid stenosis, for which management is currently at a turning point. Improved control of blood pressure, smoking ban campaigns, and the widespread use of statins have reduced the risk of cerebral infarction to <1% per year. However, about 15% of strokes are still secondary to a carotid stenosis, which can potentially be detected by effective imaging techniques. For symptomatic carotid stenosis, current ESC guidelines put a threshold of 70% for formal indication for revascularization. A revascularization should be discussed for symptomatic stenosis over 50% and for asymptomatic carotid stenosis over 60%. This evaluation should be performed by ultrasound as a first-line examination. As a complement, computed tomography angiography (CTA) and/or magnetic resonance angiography are recommended for evaluating the extent and severity of extracranial carotid stenosis. In perspective, new high-risk markers are currently being developed using markers of plaque neovascularization, plaque inflammation, or plaque tissue stiffness. Medical management of patient with carotid stenosis is always warranted and applied to any patient with atheromatous lesions. Best medical therapy is based on cardiovascular risk factors correction, including lifestyle intervention and a pharmacological treatment. It is based on the tri-therapy strategy with antiplatelet, statins, and ACE inhibitors. The indications for carotid endarterectomy (CEA) and carotid artery stenting (CAS) are similar: for symptomatic patients (recent stroke or transient ischaemic attack ) if stenosis >50%; for asymptomatic patients: tight stenosis (>60%) and a perceived high long-term risk of stroke (determined mainly by imaging criteria). Choice of procedure may be influenced by anatomy (high stenosis, difficult CAS or CEA access, incomplete circle of Willis), prior illness or treatment (radiotherapy, other neck surgery), or patient risk (unable to lie flat, poor AHA assessment). In conclusion, neither systematic nor abandoned, the place of carotid revascularization must necessarily be limited to the plaques at highest risk, leaving a large place for optimized medical treatment as first line management. An evaluation of the value of performing endarterectomy on plaques considered to be at high risk is currently underway in the ACTRIS and CREST 2 studies. These studies, along with the next result of ACST-2 trial, will provide us a more precise strategy in case of carotid stenosis.

Overall survival and mortality risk factors in Takayasu's arteritis: A multicenter study of 318 patients.

OBJECTIVE: To report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors. METHODS: We analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25-47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model. RESULTS: Among 318 TA patients, 16 (5%) died after a median [IQR] follow-up of 6.1 [2.8-13.0] years. The median age at death was 38 [25-47] years with 88% of women. Main causes of death included mesenteric ischemia (n = 4, 25%) and aortic aneurysm rupture (n = 4, 25%). The mortality rate at 5 and 10 years was of 1.9% and 3.9%, respectively. Caucasians (p = 0.049) and smokers (p = 0.002) TA patients were more likely to die. There was an increased mortality in TA (SMR with 95% confidence interval, 2.73 [1.69-4.22]) as compared to age and sex matched healthy controls. We defined high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). In the high risk TA group, the 5-year incidence of death and vascular complication was 48.5% compared to 21.6% (p = 0.001) in those with low risk. CONCLUSION: The overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. We identified specific characteristics that distinguish TA patients at highest risk for death and vascular complications.

Analysis of aortic pressure fields from 4D flow MRI in healthy volunteers: Associations with age and left ventricular remodeling.

BACKGROUND: Aging-related arterial stiffness is associated with substantial changes in global and local arterial pressures. The subsequent early return of reflected pressure waves leads to an elevated left ventricular (LV) afterload and ultimately to a deleterious concentric LV remodeling. PURPOSE: To compute aortic time-resolved pressure fields of healthy subjects from 4D flow MRI and to define relevant pressure-based markers while investigating their relationship with age, LV remodeling, as well as tonometric augmentation index (AIx) and pulse wave velocity (PWV). STUDY TYPE: Retrospective. POPULATION: Forty-seven healthy subjects (age: 49.5 ± 18 years, 24 women). FIELD STRENGTH/SEQUENCE: 3 T/4D flow MRI. ASSESSMENT: Spatiotemporal pressure fields were computed by integrating velocity-derived pressure gradients using Navier-Stokes equations, while assuming zero pressure at the sino-tubular junction. To quantify aortic pressure spatiotemporal variations, we defined the following markers: 1) volumetric aortic pressure propagation rates ΔP E1 /ΔV and ΔP E2 /ΔV, representing variations of early and late systolic relative pressure peaks along the aorta, respectively, according to the cumulated aortic volume; 2) ΔA PE1-PE2 defined in four aortic regions as the absolute difference between early and late systolic relative pressure peaks amplitude. STATISTICAL TESTS: Linear regression, Wilcoxon rank sum test, Bland-Altman analysis, and intraclass correlation coefficients (ICC). RESULTS: Spatiotemporal variations of aortic pressure peaks were moderately to highly reproducible (ICC ≥0.50) and decreased significantly with age, in terms of absolute magnitude: ΔP E1 /ΔV (r = 0.70, P < 0.005), ΔP E2 /ΔV (r = -0.45, P < 0.005) and ΔA PE1-PE2 (|r| > 0.39, P < 0.005). ΔP E1 /ΔV was associated with LV remodeling (r = 0.53, P < 0.001) and ascending aorta ΔA PE1-PE2 was associated with AIx (r = -0.59, P < 0.001). Both associations were independent of age and systolic blood pressures. Only weak associations were found between pressure indices and PWV (r ≤ 0.40). DATA CONCLUSION: 4D flow MRI relative aortic pressures were consistent with physiological knowledge as demonstrated by their significant volumetric and temporal variations with age and their independent association with LV remodeling and augmentation index. Level of Evidence 2 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2019;50:982-993.

Comparison of different methods for the estimation of aortic pulse wave velocity from 4D flow cardiovascular magnetic resonance.

BACKGROUND: Arterial pulse wave velocity (PWV) is associated with increased mortality in aging and disease. Several studies have shown the accuracy of applanation tonometry carotid-femoral PWV (Cf-PWV) and the relevance of evaluating central aorta stiffness using 2D cardiovascular magnetic resonance (CMR) to estimate PWV, and aortic distensibility-derived PWV through the theoretical Bramwell-Hill model (BH-PWV). Our aim was to compare various methods of aortic PWV (aoPWV) estimation from 4D flow CMR, in terms of associations with age, Cf-PWV, BH-PWV and left ventricular (LV) mass-to-volume ratio while evaluating inter-observer reproducibility and robustness to temporal resolution. METHODS: We studied 47 healthy subjects (49.5 ± 18 years) who underwent Cf-PWV and CMR including aortic 4D flow CMR as well as 2D cine SSFP for BH-PWV and LV mass-to-volume ratio estimation. The aorta was semi-automatically segmented from 4D flow data, and mean velocity waveforms were estimated in 25 planes perpendicular to the aortic centerline. 4D flow CMR aoPWV was calculated: using velocity curves at two locations, namely ascending aorta (AAo) and distal descending aorta (DAo) aorta (S1, 2D-like strategy), or using all velocity curves along the entire aortic centreline (3D-like strategies) with iterative transit time (TT) estimates (S2) or a plane fitting of velocity curves systolic upslope (S3). For S1 and S2, TT was calculated using three approaches: cross-correlation (TTc), wavelets (TTw) and Fourier transforms (TTf). Intra-class correlation coefficients (ICC) and Bland-Altman biases (BA) were used to evaluate inter-observer reproducibility and effect of lower temporal resolution. RESULTS: 4D flow CMR aoPWV estimates were significantly (p < 0.05) correlated to the CMR-independent Cf-PWV, BH-PWV, age and LV mass-to-volume ratio, with the strongest correlations for the 3D-like strategy using wavelets TT (S2-TTw) (R = 0.62, 0.65, 0.77 and 0.52, respectively, all p < 0.001). S2-TTw was also highly reproducible (ICC = 0.99, BA = 0.09 m/s) and robust to lower temporal resolution (ICC = 0.97, BA = 0.15 m/s). CONCLUSIONS: Reproducible 4D flow CMR aoPWV estimates can be obtained using full 3D aortic coverage. Such 4D flow CMR stiffness measures were significantly associated with Cf-PWV, BH-PWV, age and LV mass-to-volume ratio, with a slight superiority of the 3D strategy using wavelets transit time (S2-TTw).

Peripheral arterial disease and systematic detection of circulating tumor cells: rationale and design of the DETECTOR prospective cohort study.

BACKGROUND: Smoking is a strong risk factor for cancer and atherosclerosis. Cancer mortality, especially from lung cancer, overtakes cardiovascular (CV) death rate in patients with peripheral arterial disease (PAD). Only a few patients with lung cancer after PAD management may benefit from surgical excision. Circulating tumor cells (CTC) associated with low-dose chest CT (LDCT) may improve early cancer detection. This study focuses on a screening strategy that can address not only lung cancer but all tobacco-related cancers in this high-risk population. METHODS: DETECTOR Project is a prospective cohort study in two French University hospitals. Participants are smokers or former smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 to 80 years, with atherosclerotic PAD or abdominal aortic aneurysm. After the first screening round combining LDCT and CTC search on a blood sample, two other screening rounds will be performed at one-year interval. Incidental lung nodule volume, volume doubling time and presence of CTC will be taken into consideration for adapted diagnostic management. In case of negative LDCT and presence of CTC, a contrast enhanced whole-body PET/CT will be performed for extra-pulmonary malignancy screening. Psychological impact of this screening strategy will be evaluated in population study using a qualitative methodology. Assuming 10% prevalence of smoking-associated cancer in the studied population, a total of at least 300 participants will be enrolled. DISCUSSION: Epidemiological data underline an increase incidence in cancer and related death in the follow-up of patients with PAD, compared with the general population, particularly for tobacco-related cancers. The clinical benefit of a special workup for neoplasms in patients with PAD and a history of cigarette smoking has never been investigated. By considering CTCs detection in this very high-risk selected PAD population for tobacco-induced cancer, we expect to detect earlier pulmonary and extra-pulmonary malignancies, at a potentially curable stage. TRIAL REGISTRATION: The study was registered in the French National Agency for Medicines and Health Products Safety (No N° EUDRACT_ID RCB: 2016-A00657-44) and was approved by the ethics Committee for Persons Protection (IRB number 1072 and n° initial agreement 2016-08-02; ClinicalTrials.gov identifier NCT02849041).

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.

Long-Term Outcomes and Prognostic Factors of Complications in Takayasu Arteritis: A Multicenter Study of 318 Patients.

BACKGROUND: Because of the wide variation in the course of Takayasu arteritis (TA), predicting outcome is challenging. We assess long-term outcome and prognosis factors for vascular complications in patients with TA. METHODS: A retrospective multicenter study of characteristics and outcomes of 318 patients with TA fulfilling American College of Rheumatology and Ishikawa criteria was analyzed. Factors associated with event-free survival, relapse-free survival, and incidences of vascular complications were assessed. Risk factors for vascular complications were identified in a multivariable model. RESULTS: The median age at TA diagnosis was 36 [25-47] years, and 276 patients (86.8%) were women. After a median follow-up of 6.1 years, relapses were observed in 43%, vascular complications in 38%, and death in 5%. Progressive clinical course was observed in 45%, carotidodynia in 10%, and retinopathy in 4%. The 5- and 10-year event-free survival, relapse-free survival, and complication-free survival were 48.2% (42.2; 54.9) and 36.4% (30.3; 43.9), 58.6% (52.7; 65.1) and 47.7% (41.2; 55.1), and 69.9% (64.3; 76.0) and 53.7% (46.8; 61.7), respectively. Progressive disease course (P=0.018) and carotidynia (P=0.036) were independently associated with event-free survival. Male sex (P=0.048), elevated C-reactive protein (P=0.013), and carotidynia (P=0.003) were associated with relapse-free survival. Progressive disease course (P=0.017), thoracic aorta involvement (P=0.009), and retinopathy (P=0.002) were associated with complication-free survival. CONCLUSIONS: This nationwide study shows that 50% of patients with TA will relapse and experience a vascular complication ≤10 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications.

Evaluation of a new model of hind limb ischemia in rabbits.

OBJECTIVE: Various animal models of critical limb ischemia have been developed in the past. However, there is no animal model that can undergo endovascular treatment, while providing reproducible true critical limb ischemia with arterial ulcers and rest pain. We evaluated the efficacy of a new model of rabbit hindlimb ischemia created through a percutaneous approach using embolization with calibrated particles. METHODS: Through a percutaneous transauricular artery approach and selective catheterization of the superficial femoral artery, embolization of distal limb vessels was performed using a mixture of 300- to 500-µm calibrated microparticles (Embosphere, Merit Medical, Salt Lake City, Utah), saline solution, and iodine contrast. Clinical and ultrasound imaging-based blood flow evaluation was performed before embolization and during follow-up. Histologic evaluation was performed at humane killing 14 days after the procedure. RESULTS: The model was successfully created in 10 rabbits (10 limbs). One rabbit died of sudden death at 8 days after the procedure. The nine surviving rabbits developed hind ulcers. All rabbits had a higher pain score in the follow-up compared to baseline value (P < .0001). Blood flow in the saphenous artery decreased significantly after the procedure and later at 14 days follow-up (baseline value 63.4 ± 31.3 µL per cardiac cycle vs 32.0 ± 28.4 µL per cardiac cycle postprocedure [P = .0013] and 32.0 ± 28.4 µL per cardiac cycle at 14 days [P = .0015]). Pathology showed signs of severe limb ischemia in all rabbits with subacute and chronic injury patterns. CONCLUSIONS: A rabbit hind limb ischemia model created by percutaneous transauricular distal femoral artery embolization with calibrated particles may overcome some of the limitations of existing animal models. As such, this model could prove useful for assessing therapies designed to improve arterial perfusion and collateral growth.

Efficacy of Biological-Targeted Treatments in Takayasu Arteritis: Multicenter, Retrospective Study of 49 Patients.

BACKGROUND: The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis. METHODS AND RESULTS: This was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20-55 years] treated by tumor necrosis factor-α antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1-5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10-46 mg/L] versus 58 mg/L [26-76 mg/L]; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [P<0.05] and 15 versus 7.5 mg [P<0.05] at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%-99%) over the biological treatment period compared with 58.7% (43.3%-79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2-95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases. CONCLUSION: This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.

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.