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International audience; Objectives: Pulse wave velocity (PWV) of the aortic arch is usually estimated by using 2D phase contrast in MRI. Thanks to 4D flow MRI, segmental PWV of the ascending and descending aorta, as well as PWV of the entire thoracic aorta can now be estimated within the same examination. Our objective is to compare PWVs obtained by 2D and 4D PC, through their relationships with carotid-femoral PWV (cf-PWV), age and left ventricular remodelling.Basic methods: MRI examinations were performed at 3 Tesla, including 2D PC acquisitions with through-plane velocity encoding and sagittal 4D phase contrast acquisitions covering the thoracic aorta volume. PWVs were calculated after estimating aortic lengths and flow transit times between the ascending aorta and descending aorta in 2D and between valve, isthmus and diaphragm in 4D resulting in 2D-PWV, 4D-TA-PWV; 4D-AA-PWV, 4D-DA-PWV.Main results: Fifty-seven healthy volunteers (25 men, age 51 years ± 17) were studied. All MRI-PWVs were correlated with cf-PWV (r = 0.67; r = 0.63: r = 0.47; r = 0.61 for 2D-PWV, 4D-TA-PWV; 4D-AA-PWV, 4D-DA-PWV, respectively, P < 0.001). 2D-PWV and 4D-TA-PWV were strongly related with age (r = 0.76 and r = 0.77, respectively). The highest correlation, between left ventricular thickness or LV mass/end diastolic volume (EDV) ratio and segmental PWVs of the thoracic aorta was found with 4D-AA-PWV (r = 0.43, P < 0.01 and r = 0.48, P < 0.01).Principal conclusions: Global and segmental PWV analysis of the thoracic aorta can be accurately assessed using 4D flow MRI. 4D-PWVs were highly correlated with ageing and cf-PWV. The strong association between the ascending aorta stiffness and the left ventricular remodelling in healthy volunteers is encouraging to better estimate left ventricular afterload.

Background: Not all patients with severe aortic valve stenosis are eligible for open-heart surgery or TAVR. CARDIAWAVE (Paris, France) has developed Valvosoft, a unique non-invasive ultrasound therapy device to treat aortic stenosis. The therapy aims to improve the opening of severely calcified aortic valves by cracking the calcium and reducing the stiffness in the aortic valve tissue by delivering transthoracically local shock waves on the valve leaflets. This study assesses the safety, feasibility and performance of this novel technique. Methods: This is a multi-center, prospective, first-in-man study designed to evaluate the safety and feasibility of the Valvosoft device. Ten patients with severe symptomatic calcific aortic stenosis and not eligible for SAVR/TAVR underwent a Valvosoft ultrasound therapy. Echocardiographic evaluation was performed by an independent core lab at baseline, discharge, and at 1, 3, 6 and 12 months along with clinical follow up. Results: Enrolled patients were advanced in age (84.1±6.5 yrs) with severe comorbidities (8 with heart failure, 5 with coronary heart disease and 5 with kidney failure). All had extensive aortic valve calcification with mean AVA of 0.61±0.17 cm2 and mean pressure gradient of 37.5±10.5 mmHg. At one-month follow-up, six patients had significantly improved their AVA with increase of 27.5% (p=0.03) and mean pressure gradient decrease of 23.2 % (p=0.025). These patients also received the highest dose and longest treatment duration. During one year follow up, 4 patients died due to progression of end stage heart failure not linked to the procedure and one patient had undergone a TAVR procedure. At 12 months, the five remaining patients has no device or procedure related major adverse events nor deterioration of neurological status. Echo, brain-MRI and clinical follow up will be presented. Conclusions: Non-invasive ultrasound therapy is feasible and safe in patients with severe aortic valve stenosis and can improve AVA and hemodynamic parameters. NIUT can be an important tool complementary to TAVI in treating patients with aortic valve stenosis.

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.

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 P 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.

Vascular Ehlers–Danlos syndrome is a dramatic inherited disease caused by mutations of type III collagen ( COL3A1 ) gene, associated with early-onset occurrence of arterial ruptures. Col3a1 +/− heterozygous mice, the only vascular Ehlers–Danlos syndrome model available to date, have no spontaneous early vascular phenotype. Our objective was to determine the susceptibility of Col3a1 +/− mice to develop arterial ruptures under high blood pressure (BP) conditions induced by a 4-week infusion of angiotensin II (AngII). AngII (1 μg/kg per minute) significantly and comparably increased systolic BP in Col3a1 +/− and Col3a1 +/+ mice but led to a higher premature mortality rate in Col3a1 +/− mice compared with Col3a1 +/+ mice (73% versus 36%; P =0.03), particularly during the first-week infusion (55% versus 0%). Echocardiography and histological analysis evidenced that early deaths were caused by thoracic aortic ruptures preceded by dissections and associated with low aortic collagen fibrils content. Remarkably, lowering the dose of AngII (0.5 μg/kg per minute) rescued the first-week premature deaths of Col3a1 +/− mice while decreasing the rises in systolic BP ( P =0.05 compared with the high-dose AngII), resulting in similar mortality rates in both groups of mice at the end of the 4-week period (30% versus 50% in Col3a1 +/− and Col3a1 +/+ mice; P =0.30). Finally, norepinephrine infusion (3.9 μg/kg per minute) did not induced significant mortality in both groups, whereas it significantly increased systolic BP, comparably with the high and with the low dose of AngII in Col3a1 +/− mice ( P =0.53 and P =1.00, respectively). Our findings demonstrated the extreme sensitivity of Col3a1 insufficient mice to prematurely develop thoracic aortic ruptures in response to AngII and its associated high levels in BP.

Background— One of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. Methods and Results— A posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting ( P P P P Conclusions— Reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

Background—Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)–enhanced atherogenesis.Methods and Results—Ten-week-old ApoE+/−mice lacking either 1 IL-1R1 allele (ApoE+/−/IL-1R1+/−) or 2 IL-1R1 alleles (ApoE+/−/IL-1R1−/−) fed either an HFD or regular chow were inoculated intravenously with livePorphyromonas gingivalis(P gingivalis) (107CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE+/−/IL-1R1−/−mice than in ApoE+/−/IL-1R1+/−mice challenged withP gingivalis.At 24 weeks afterP gingivalisinoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold–reduced in chow-fed ApoE+/−/IL-1R1−/−mice than in ApoE+/−/IL-1R1+/−mice (P+/−/IL-1R1−/−mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and withoutP gingivalisinoculation (PConclusion—Ablation of IL-1R1 underP gingivalischallenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.

Lower extremity peripheral artery disease (PAD) is one manifestation of atherosclerosis. Patients with PAD have an increased rate of mortality due to concurrent coronary artery disease and hypertension. Betablockers (BB) may, therefore, be prescribed, especially in case of heart failure. However, BB safety in PAD is controversial, because of presumed peripheral hemodynamic consequences of BB that could lead to worsening of symptoms in patients with PAD. In this context, we aimed to determine the impact of BB on all-cause and cardiovascular mortality and amputation rate at 1 year after hospitalization for PAD from the COPART Registry population. This is a prospective multicenter observational study collecting data from consecutive patients hospitalized for PAD in vascular medicine departments of 4 academic hospitals in France. Patients with, either claudication, critical limb ischemia or acute lower limb ischemia related to a documented PAD were included. We compared the outcomes of patients with BB versus those without BB in their prescription list at hospital discharge. The mean age of the study population was 70.9 years, predominantly composed of males (71%). Among the 1267 patients at admission, 28% were treated by BB for hypertension, prior myocardial infarction or heart failure. During their hospital stay, 40% underwent revascularization (including bypass surgery 29% and angioplasty 74%), 17% required an amputation, and 5% died. In a multivariate analysis, only prior myocardial infarction was found associated with BB prescription with an odds ratio (OR) of 3.11, P

Background Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone. Methods and Results We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2±2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2±0.3 to 1.4±0.3 mL; +3.8±0.5 mm to −2.2±0.7 mm axially relative to baseline; P P Conclusions PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.

To the Editor: In their recent article in Circulation , De Varennes et al1 proposed to test the efficacy of posterior leaflet extension with remodeling annuloplasty on 44 patients with type IIIb ischemic mitral regurgitation (MR). In their introduction, the authors explain that most often ischemic MR mechanism is complex, “and the resulting MR jet is composed of a central and posteriorly directed jet of regurgitation (Carpentier type I and III).” In the discussion, the authors further explain …

Background. We have previously demonstrated that severing two second-order chordae to the anterior mitral leaflet (AL) in sheep does not adversely affect LV size and function acutely. Objectives. This study tested whether chordal cutting exacerbates long-term LV remodeling when applied to treat ischemic mitral regurgitation (MR) in a chronic myocardial infarction (MI). Methods. A posterolateral MI was created in 18 sheep by ligation of obtuse marginal branches. After chronic remodeling and MR development at 2 months, sheep were randomized to sham surgery versus anterior leaflet (AntL) or bileaflet (BiL) second-order chordal cutting (n=6 each), techniques in clinical application. 2D and 3D echo at baseline, chronic infarction (2 months), and follow-up at a mean of 6.5 months post-MI (sacrifice) measured LV end-diastolic and end-systolic volume (EDV and ESV), ejection fraction (EF), wall motion score index (WMSi), and posterior leaflet (PL) restriction angle relative to the annulus. Results. All measurements were comparable among groups at baseline and chronic MI. At sacrifice, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased by 33.0±7.2% and 28.0±5.0% relative to chronic MI with AntL and BiL chordal cutting, versus 109.0±8.7% in controls (p Conclusions: Cutting secondary chordae in the chronic post-MI setting does not adversely affect long-term LV remodeling, and limits progressive increases in LV volumes.

Background— Skeletal myoblast (SM) transplantation (Tx) in a post-myocardial infarction (MI) scar experimentally improves left ventricular (LV) ejection fraction (EF). Short-term follow-up (FU) studies have suggested that a similar benefit could clinically occur despite an increased risk of LV arrhythmias. Methods and Results— We report the long-term FU of the first worldwide cohort of grafted patients (n =9, 61.8±11.6 years, previous MI, EF ≤35%) operated on (autologous SM Tx and bypass surgery) in 2000 to 2001 and evaluated before Tx, at 1 month (M1) and at a median FU of 52 (18 to 58) months after Tx (37 patient-years). NYHA class improved from 2.5±0.5 to 1.8±0.4 at M1 ( P =0.004 versus baseline) and 1.7±0.5 at FU ( P =not significant versus M1; P =0.0007 versus baseline). EF increased from 24.3±4% to 31±4.1% at M1 (+28%, P =0.001 versus baseline) and remained stable thereafter (28.7±8.1%, +18% versus baseline). There were 5 hospitalizations for heart failure in 3 patients at 28.6±9.9 months, allowing implant in 2 patients with a resynchronization pacemaker. An automatic cardiac defibrillator (ACD) was implanted in 5 patients for nonsustained (n =1) or sustained (n =4) ventricular tachycardia at 12.2±18.6 (1 to 45) months. Despite a beta-blocker/amiodarone combination therapy, there were 14 appropriate shocks for 3 arrhythmic storms in 3 patients at 6, 7, and 18 months after ACD implantation. Conclusions— In this cohort of severe heart failure patients both clinical status and EF stably improve over time with a strikingly low incidence of hospitalizations for heart failure (0.13/patient-years) and the arrhythmic risk can be controlled by medical therapy and/or on-request ACD implantation.

Background— Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Leaflet closure is restricted by tethering to displaced papillary muscles, and is, therefore, incompletely treated by annular reduction. In an acute ischemic model, we reduced such MR by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. Whether this is effective without prolapse, recurrent MR, or left ventricular (LV) failure in chronic persistent ischemic MR, despite greater LV remodeling, remains to be established. Therefore, we studied 7 sheep with chronic inferobasal infarcts known to produce progressive MR over 2 months. In all of those sheep, after a mean of 4.1 months, the 2 central basal (intermediate) chordae were cut at the chronic ischemic MR stage. 3-Dimensional echo quantified MR, LV function, and valve geometry. Five other sheep were followed for a mean of 7.8±1.2 months after inferobasal infarction with chordal cutting. Results— All 7 of the sheep with chronic ischemic MR (increased from 1.4±0.4 to 11.1±0.5 mL/beat, regurgitant fraction=39.0±4.2%, P P P =not significant [NS]). The five sheep with long-term follow-up showed no prolapse or MR, and no significant post-infarct decrease in LV ejection fraction (EF; 38.9±2.4% to 41.4±1.2%, P =NS). Conclusion— Cutting a minimum number of basal (intermediate) chordae can improve coaptation and reduce chronic persistent ischemic MR without impairing LVEF. No adverse effects were noted long-term after chordal cutting at the time of infarction.

Background—Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique.Methods and Results—Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300,P=0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5×106, n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean±SEM) was increased only in the cultured SM–transplanted group at 1 (P=0.0006) and 2 months (P=0.0008) versus baseline (37.52±1.92 and 40.92±2.17 versus 30.34±1.74), with a significant additional benefit between 1 and 2 months (P=0.0069).Conclusions—Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.