P4490Safety and feasibility of non invasive transthoracic pulsed cavitational ultrasound therapy (PCUT) on a swine aortic valve model

Abstract

Background Aortic valve stenosis is associated with age and comorbidities, which require exploring less invasive therapeutic approach to improve patient outcome. We previously demonstrated in vitro and in vivo that pulsed cavitational ultrasound therapy (PCUT) can improve calcified bioprosthesis stenosis by softening leaflets remotely. To apply this technique noninvasively we aim to test PCUT transthoracicalyin a swine model targeting aortic valve. Because calcified aortic valve model doesn't exist, we tested this technique on a normal valve. Objective Primary objective was to estimate the feasibility and safety of PCUT. Secondary objectiveswere to evaluate occurrence, severity and evolution of cardiovascular side effects during therapy and within follow-up period (30±5 days) with and without double antithrombotic treatment. Methods All the experiments were performed on normal aortic valves (n=19) of swine. The system was composed of a high-power multi-element transducer with electronic steering and 2D echocardiographic probe embedded in the center. Swine were divided in three groups: one with PCUT and no anti thrombotic treatment (n=10), a second with PCUT and one-month treatment of aspirin and clopidogrel (n=5) and third group sham (n=4). All groups were followed up after 30 days. Results The primary feasibility endpoint was successful in 100% of tests performed (n=16). A maximal amplitude of 70 MPa and −19 MPa respectively for positive and negative peak pressure was found at the focus point. Survival at 30 days was 100% and no life-threatening arrhythmia was recorded and no sustained ventricular arrhythmia (SVT >30 s) was noticed. For the secondary safety objectives,we recorded acutely, at the time of procedure, NSVT in 7 pigs which corresponded to a cumulated duration of 2.1 out of the 485.3 min of the total US delivery (0.4% of time). Mean cycle of NSVT was slow 428.9 ms in average (139.6 bpm). The interruption or decrease of power of US delivery allowed immediate cessation of cardiac arrhythmia in all cases. There was no evidence of damage to the valve and no observation of impairment of valvular function by echocardiography. Only one animal showed side effects (RV dilatation) and the RV returned to normal after cessation of the therapy with no sequelae at follow up. At follow up no significant findings biology disturbance or valve thrombosis was observed (creatinine, CK MB, hemoglobin, hematocrit, haptoglobin or red blood cell numbers). Antithrombotic treatment didn't demonstrate any advantage at follow up. Conclusion We demonstrated in vivo feasibility and safety of transthoracic PCUT targeting aortic valve without any serious adverse event and no significant histopathology damage. We hope that this first-time transthoracic delivery of very focused ultrasound at high power will pave the way to new non invasive approach of valve softening in case of human aortic valve calcified stenosis.