Feasibility and Performance of Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve Stenosis

HomeCirculationVol. 143, No. 9Feasibility and Performance of Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve Stenosis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBFeasibility and Performance of Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve StenosisA First-in-Human Study Emmanuel Messas, MD, PhD, Alexander IJsselmuiden, MD, PhD, Guillaume Goudot, MD, PhD, Selina Vlieger, MSc, Samuel Zarka, MD, Etienne Puymirat, MD, PhD, Bernard Cholley, MD, PhD, Christian Spaulding, MD, PhD, Albert A. Hagège, MD, PhD, Eloi Marijon, MD, PhD, Mickael Tanter, PhD, Benjamin Bertrand, MSF, Mathieu C. Rémond, DSc, Robin Penot, MSc, B. Ren, MD, PhD, Peter den Heijer, MD, PhD, Mathieu Pernot, PhD and René Spaargaren, MD Emmanuel MessasEmmanuel Messas Emmanuel Messas, MD, PhD, Hôpital Européen Georges Pompidou, Université Paris Descartes, Cardio-Vascular Departement, UMR 970, Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3214-7501 Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. French Research Consortium RHU STOP-AS, Rouen, France. (E. Messas, B.B., M.C.R., R.P., R.S.). , Alexander IJsselmuidenAlexander IJsselmuiden Heart Center, Amphia Hospital, Breda, The Netherlands (A.I., S.V., P.d.H.). , Guillaume GoudotGuillaume Goudot Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Selina VliegerSelina Vlieger Heart Center, Amphia Hospital, Breda, The Netherlands (A.I., S.V., P.d.H.). , Samuel ZarkaSamuel Zarka Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Etienne PuymiratEtienne Puymirat Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Bernard CholleyBernard Cholley https://orcid.org/0000-0001-6388-6011 Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. Anesthesiology and Critical Care Department, Hôpital Européen Georges-Pompidou (B.C.), APHP Université de Paris, France. , Christian SpauldingChristian Spaulding Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Albert A. HagègeAlbert A. Hagège Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Eloi MarijonEloi Marijon Cardiovascular Department (E. Messas, G.G., S.Z., E.P., B.C., C.S., A. A.A.H., E. Marijon), APHP Université de Paris, France. , Mickael TanterMickael Tanter Physics for Medicine, U1273 INSERM, ESPCI Paris, CNRS, PSL Research University, France (M.T., M.P.). , Benjamin BertrandBenjamin Bertrand Cardiawave, Paris, France (B.B., M.C.R., R.P., R.S.). French Research Consortium RHU STOP-AS, Rouen, France. (E. Messas, B.B., M.C.R., R.P., R.S.). , Mathieu C. RémondMathieu C. Rémond Cardiawave, Paris, France (B.B., M.C.R., R.P., R.S.). French Research Consortium RHU STOP-AS, Rouen, France. (E. Messas, B.B., M.C.R., R.P., R.S.). , Robin PenotRobin Penot Cardiawave, Paris, France (B.B., M.C.R., R.P., R.S.). French Research Consortium RHU STOP-AS, Rouen, France. (E. Messas, B.B., M.C.R., R.P., R.S.). , B. RenB. Ren Cardialysis, Rotterdam, The Netherlands (B.R.). , Peter den HeijerPeter den Heijer Heart Center, Amphia Hospital, Breda, The Netherlands (A.I., S.V., P.d.H.). , Mathieu PernotMathieu Pernot Physics for Medicine, U1273 INSERM, ESPCI Paris, CNRS, PSL Research University, France (M.T., M.P.). and René SpaargarenRené Spaargaren Cardiawave, Paris, France (B.B., M.C.R., R.P., R.S.). French Research Consortium RHU STOP-AS, Rouen, France. (E. Messas, B.B., M.C.R., R.P., R.S.). Originally published25 Jan 2021https://doi.org/10.1161/CIRCULATIONAHA.120.050672Circulation. 2021;143:968–970Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 25, 2021: Ahead of Print Calcific aortic stenosis (CAS) is currently the most common heart valve disease. To date, surgical or transcatheter aortic valve replacement is the only effective treatment. However, 16% of patients with symptomatic severe CAS are rejected by local heart teams for surgical or transcatheter aortic valve replacement.1 Valvosoft (Cardiawave) is a device designed to improve the function of calcified aortic valves (AVs) with noninvasive ultrasound therapy (NIUT).2 On the basis of preclinical results,2,3 a prospective first-in-human study was conducted in 2 centers (Hôpital Européen Georges-Pompidou, France; Amphia Hospital, Breda, The Netherlands) in 10 patients with symptomatic severe CAS who were not eligible for AV replacement according to local heart teams (mainly because of comorbidities, vascular access, and life expectancy <12 months; https://www.clinicaltrials.gov, NCT03779620). The study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committees of both participating centers and the competent authorities of The Netherlands and France. All patients provided written informed consent.The mechanism of action of NIUT consists of generating microscopic cavitation bubbles with short, high-pressure ultrasound pulses focused on the AV. As cavitation bubbles collapse, they produce shock waves inducing mechanical softening of the targeted calcified valve leaflet. Therapeutic dose was estimated as the mean acoustic focal energy (J/mm2) that integrates focal intensity over procedure duration.Data were presented as mean±SD for continuous variables and number and percentage for categorical data. Paired-sample t test or independent-sample t test, when appropriate, was used to compare continuous variables. Data will be made available from the corresponding author on reasonable request.Patients (mean age, 84.1±6.5 years; 50% women) had severe CAS (mean AV area, 0.61±0.18 cm2; mean pressure gradient, 37.5±10.5 mm Hg) and presented with severe comorbidities. NIUT could be delivered on the AV transthoracically in all patients using the real-time echo guiding of the device. Mean ultrasound delivery time was 52 minutes (range, 37–60 minutes), and mean acoustic focal energy delivered on the AV was 221±87 J/mm2.Seven patients were treated in a hybrid operating room and 3 in a catheterization laboratory. During the procedure, 1 patient developed atrial fibrillation, which spontaneously converted to sinus rhythm within minutes, and 7 patients had a few premature ventricular beats. Two patients had nonsustained ventricular tachycardia that lasted <4 seconds; this was hemodynamically well tolerated and resolved spontaneously. Events such as arrhythmia and chest wall discomfort from transducer pressure were managed with sedation or analgesia combined with short pauses in ultrasound application. Six patients were treated without general anesthesia, 4 of them without sedation. No deaths, myocardial infarctions, strokes, or transient ischemic attacks were reported at the 1-month follow-up. Patient 2 was hospitalized 2 weeks after the procedure for right-sided heart failure, which resolved and was adjudicated not to be procedure or device related.Clinical and echocardiographic evaluation was performed by an independent core laboratory. No significant difference between baseline and follow-up at 1 month was observed in the Mini-Mental State Examination score, suggesting that the cognitive function was not impaired. New-onset or worsening aortic regurgitation was not detected. No changes in left ventricular function and volumes were observed. For the overall population, a nonsignificant increase in AV area of 16.4% (0.61 cm2 versus 0.71 cm2; P=0.112) and a nonsignificant decrease in mean pressure gradient of 12.5% (37.5 mm Hg versus 32.8 mm Hg; P=0.191) were observed (Figure [A]). Figure (B) shows the wide variability in treatment response. Six patients were responders (patients 2–4 and 8–10) with an increase in AV area of 27.6% (P=0.03), associated with a decrease in mean pressure gradient of 23.5% (P=0.03). The duration of therapy was significantly longer in the responder group than in the nonresponder group (56.8±3.7 minutes versus 44.4±7.0 minutes; P<0.05), and the cumulative focal energy delivery was >180 J/mm2 (Figure [C]). Post hoc exploratory analysis attempting to identify factors potentially associated with treatment response suggests that a minimum treatment duration and focal energy may be needed to obtain a clinical effect.Download figureDownload PowerPointFigure. Treatment characteristics and changes in AVA and mean PG.A, Percent changes in aortic valve area (AVA) and mean pressure gradient (PG) at 1 month with respect to baseline for all patients. B, Change in AVA and mean PG for all patients. Patients were defined as responders if they showed an increase in AVA and a decrease in mean PG with improvement or stabilization of New York Heart Association class at 1 month after the procedure compared with baseline. Responders are represented as blue diamonds (top left); nonresponders are represented as orange circles. C, Responders and nonresponders are plotted as a function of treatment duration and focal energy. All 6 responders received >180 J/mm2 for at least 45 minutes. Of the 4 non-responders, 3 received less focal energy or energy for a duration <45 minutes; 1 nonresponder is on the border of the specified area. NIUT indicates noninvasive ultrasound therapy.NIUT is noninvasive, unlike other devices using similar concepts of calcium fragmentation,4 and can be performed without general anesthesia.Overall, current clinical data show that NIUT was feasible in 10 patients with severe CAS. Ongoing clinical studies are assessing its safety and the effects of higher energy doses. Current results reflect only 1-month outcomes and do not address safety and durability of the therapy. Brain magnetic resonance imaging was not performed in this study; therefore, silent cerebrovascular events5 cannot be ruled out.In conclusion, NIUT was feasible in this small cohort of 10 patients with severe CAS. Patients with the longest therapy time and highest energy levels showed promising results. Further studies with optimized treatment and longer follow-up are required to evaluate the safety, performance, and durability of this new technique and to determine the population benefiting most.Sources of FundingThis study has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 829492 and is supported by the French Government, managed by the National Research Agency under the “Investissements d’avenir” program (reference Nos. ANR-16-RHUS-0003 and ANR VALVOSOFT-17-CE19-0019-02).Disclosures Drs Messas, M. Pernot, and Tanter are cofounders and shareholders of Cardiawave SA. B. Bertrand is cofounder and CEO of Cardiawave SA. R. Penot, Dr Rémond, and Dr Spaargaren are employees of Cardiawave SA. The other authors report no conflicts.FootnotesRegistration: URL https://www.clinicaltrials.gov; Unique identifier: NCT03779620.https://www.ahajournals.org/journal/circEmmanuel Messas, MD, PhD, Hôpital Européen Georges Pompidou, Université Paris Descartes, Cardio-Vascular Departement, UMR 970, Paris, France. Email emmanuel.[email protected]frReferences1. Durko AP, Osnabrugge RL, Van Mieghem NM, Milojevic M, Mylotte D, Nkomo VT, Pieter Kappetein A. Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections.Eur Heart J. 2018; 39:2635–2642. doi: 10.1093/eurheartj/ehy107CrossrefMedlineGoogle Scholar2. Villemain O, Robin J, Bel A, Kwiecinski W, Bruneval P, Arnal B, Ré , mond M, Tanter M, Messas E, Pernot M. Pulsed cavitational ultrasound softening: a new noninvasive therapeutic approach for calcified bioprosthetic valve stenosis.JACC Basic Transl Sci. 2017; 2:372–383.CrossrefMedlineGoogle Scholar3. Messas E, Rémond MC, Goudot G, Zarka S, Penot R, Mateo P, Kwiecinski W, Escudero DS, Bel A, Ialy-Radio N, et al.. Feasibility and safety of non-invasive ultrasound therapy (NIUT) on an porcine aortic valve.Phys Med Biol. 2020; 65:215004. doi: 10.1088/1361-6560/aba6d3CrossrefMedlineGoogle Scholar4. Bartus K, Surve D, Sato Y, Halevi R, Kislev Y, Sax S, Markov L, Golan E, Levy R, Halon D, et al.. The LeaflexTM catheter: a novel device for treating calcific aortic stenosis: first-in-human intra-operative assessment of safety and efficacy.Struct Heart. 2020; 4:221–229. doi: 10.1080/24748706.2020.1746983CrossrefGoogle Scholar5. Nombela-Franco L, Armijo G, Tirado-Conte G. Cerebral embolic protection devices during transcatheter aortic valve implantation: clinical versus silent embolism.J Thorac Dis. 2018; 10(suppl 30):S3604–S3613. doi: 10.21037/jtd.2018.09.62CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Meng Y, Pople C, Budiansky D, Li D, Suppiah S, Lim-Fat M, Perry J, Sahgal A and Lipsman N (2021) Current state of therapeutic focused ultrasound applications in neuro-oncology, Journal of Neuro-Oncology, 10.1007/s11060-021-03861-0, 156:1, (49-59), Online publication date: 1-Jan-2022. Dall’Ara G, Grotti S, Guerrieri G, Compagnone M, Spartà D, Galvani M and Tarantino F (2022) Balloon aortic valvuloplasty: current status and future prospects, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2022.2074837, 20:5, (389-402), Online publication date: 4-May-2022. Todurov B, Markovets A, Maruniak S and Demyanchuk V (2022) ULTRASONIC DECALCIFICATION OF AORTIC VALVE IN MODERN ERA: A CASE REPORT, Wiadomości Lekarskie, 10.36740/WLek202203128, 75:3, (732-734), Online publication date: 1-Mar-2022. Xu Z, Hall T, Vlaisavljevich E and Lee F (2021) Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound, International Journal of Hyperthermia, 10.1080/02656736.2021.1905189, 38:1, (561-575), Online publication date: 1-Jan-2021. Smadja D, Goudot G, Gendron N, Zarka S, Puymirat E, Philippe A, Spaulding C, Peronino C, Tanter M, Pernot M and Messas E (2021) Von Willebrand factor multimers during non-invasive ultrasound therapy for aortic valve stenosis, Angiogenesis, 10.1007/s10456-021-09803-8, 24:4, (715-717), Online publication date: 1-Nov-2021. Messas E and Goudot G (2021) La révolution des ultrasons en cardiologie et en pathologies vasculaires adultes : une épopée de plus de cinquante ans du diagnostic à la thérapie non invasive, Archives des Maladies du Coeur et des Vaisseaux - Pratique, 10.1016/j.amcp.2021.06.009, 2021:300, (28-30), Online publication date: 1-Sep-2021. March 2, 2021Vol 143, Issue 9 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.050672PMID: 33486971 Originally publishedJanuary 25, 2021 KeywordsultrasonicsaortavalvescalciumPDF download Advertisement SubjectsClinical StudiesTreatment