Evaluation Of The Efficacy Of External Ultrasound Treatment For Carotid Atherosclerotic Plaques

Part I:A Preliminary Study on the Application of External Ultrasound for Treating Carotid Atherosclerotic PlaquesBackground and objectiveIschemic stroke has become the leading cause of death and disability in China, of which about 1/3 of cases were caused by carotid atherosclerotic plaque. Carotid atherosclerotic plaque is an important risk factor for ischemic cerebrovascular disease, and meanwhile is also an indicator of coronary atherosclerosis. Carotid atherosclerotic plaques have been treated surgically or non-surgically. Surgical treatments mainly include carotid endarterectomy, angioplasty and stent placement. Carotid endarterectomy (CEA) is the best surgical treatment of carotid artery disease for it can remove the plaque completely, and has demonstrated the ability to reduce the mortality rate and disability rate. Carotid artery stenting (CAS) has become a minimally invasive, effective alternative of CEA, and may be more attractive for patients with high risk during peri operation period to avoid the operation and its related complications. But they are invasive and only suitable for patients with moderate to severe stenosis that meet indications. Drug treatment is the main non-surgical treatment, when the effect of reducing size on plaques is dissatisfactory. Previous animals and in vitro experiment studies showed that the ultrasound can selectively destruct tissues lacking normal collagen and elastic fibrous skeleton, such as thrombus and atherosclerotic plaque, whereas normal vascular wall tissues have a great elasticity because they are rich in elastic fibers, thus buffering the effect of the ultrasound, almost no damage to any layers of structures of the normal vascular wall was found with the appropriate physical parameters and operating modes were selected, the main possible mechanisms of ultrasound treatment included mechanical effect, cavitation effect etc. Ninety percent of debris of the lesion after ultrasonic treatment has a smaller diameter than that of red blood cells (larger individual debris may be caused by container contamination), they can go through the capillaries (10～20μm in diameter) and be eliminated by the reticuloendothelial system of the blood, without causing distal vascular occlusion. But most of the researches performed through interventional endovascular operation. Recently, Shehata et al have successfully used external therapeutic ultrasound for treating atherosclerotic plaques in vivo experimentation noninvasively, but it’s an experiment on animals for the femoral artery by high-intensity focused US with an integrated dual-mode US array system. In this study, the low-frequency high-energy therapeutic ultrasound was used in addition to conventional medical treatment for the patients with carotid plaques, the ultrasound head was placed on the skin surface (marked for carotid plaques) for the irradiation treatment noninvasively, and we wanted to investigate the efficacy of the external non-invasive ultrasound treatment and other factors which may affect the treatment efficacy.MethodsIn the prospective study,357 patients with 363 carotid atherosclerotic plaques were divided into an ultrasound treatment group and a control group. Conventional medical treatment was conducted on 54 plaques in the control group, while irradiation therapy was conducted on 309 plaques in the ultrasound treatment group, applying a carotid ultrasound therapy device once daily in addition to conventional medical treatment. Hitachi EUB 7000 color Doppler ultrasonic diagnostic apparatus and Philips IE33 color Doppler ultrasonic diagnostic apparatus were used for this study. The patients were arranged in the supine position. Their necks were placed on the dedicated cervical orthosis (patent number (China) ZL 2012 2 0244630.X, produced by Luoyang Kangli Medical Instrument Company Ltd.) for detecting carotid plaques and marking the projection of the plaques in the neck skin. The swivel angle of the head and the probe remained unchanged to ensure the accuracy of the ultrasonic testing before and after treatment. Ultrasound diagnosis was conducted by the experienced professional physicians who were unaware of treatment options for patients. Patients were seen by the same physician before and after treatment. Carotid ultrasonography was performed according to the operating specifications of the Chinese Ultrasound Doctors’ Association for carotid ultrasound. The size and ultrasonographic characteristics of plaques were observed and recorded. The maximum thickness and cross-sectional area of each plaque was measured in the longitudinal view. Examinations, image storing, measurement and recording were conducted before and after treatment. LHZ.B-100 ultrasound therapy device for carotid plaques (patent number ZL201120178610.2.2012-01-18, produced by Luoyang Kangli Medical Device Co., Ltd., China) was used for therapy, with an intensity at the surface of the probe 0.75-1W/cm2 (the estimated energy at the target site is similar to it),a frequency of 800 KHz, and an effective radiation area of 3 cm2. The treatment modality is pulse modulation, the pulse repetition rate is 1Hz (on-off ratio 1:1, that is working for 0.5 seconds and then stopping 0.5 seconds every second.). The beam type is divergent and the duty cycle is 50%. The necks of the patients were placed on the dedicated cervical orthosis at the same angle as before in supine position. The probe of the therapy device was fixed on the skin where it had been marked using a special head frame. Each irradiation was conducted for 30 minutes once a day during 30 days of continuous treatment. All p-values<0.05 were considered to be statistically significant. Statistical software SAS 9.4 (SAS Institute, Gary, NC) was used for all the data analysis.Results1. No patients withdrew from the treatment because of related side effects.2. After treatment, the maximum thickness and area of the 79.94% of the plaques in ultrasound group were reduced while in control group it’s 18.52%.3.The change in plaque thickness (AT) and area (△A) in the two groups were [022 ± 0.19 mm (7.61 ± 5.67%) vs.0.02 ± 0.05 mm (0.74 ± 1.64%)] and [0.047 ± 0.039 mm2 (13.28 ± 9.8%) vs.0.0044 ± 0.0102 mm2 (1.1 ± 2.46%)]. Both △T and AA in ultrasound group were significantly higher than those in control group (p<0.0001).4. Plaque echo type is a prognostic factor affecting the efficacy (p< 0.05). △ T(△Tper) and △A(△Aper) of the an-hypoechoic plaque were significantly higher that of mixed echo and calcified echo plaques.5. The size of the plaque before treatment was prognostic factors affecting the efficacy (p< 0.01). The larger the Tb and Ab, the higher the absolute value of the fall, but the percentage of the fall was not affected.6. Age, gender, smoking status, blood glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, body mass index, systolic blood pressure, diastolic blood pressure and plaque location (anterior or posterior wall) had no significant effects on the anti-plaque efficacy.Conclusion1 External ultrasound treatment combined with conventional medical treatment for carotid atherosclerotic plaques can decrease the size of the plaques, it is safe and the efficacy is better than conventional medical treatment only.2. Plaque echo type is a prognostic factor affecting the efficacy. The effect on an-hypoechoic plaque is more significant than that of mixed echo and calcified echo plaques.3 The size of the plaque before treatment is prognostic factors affecting the efficacy. The larger the size, the higher the absolute value of the fall after treatment, but the percentage of the fall was not affected.4 Age, gender, smoking status, blood glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, body mass index, systolic blood pressure, diastolic blood pressure and plaque location (anterior orPart II:The Effects of External Ultrasound for Carotid Atherosclerotic Plaques Treatment on Ultrasonographic Characteristics and Long-term changesBackground and objectiveCarotid atherosclerotic plaque is an independent risk factor for ischemic cerebrovascular disease. The main mechanism of it is intracranial arterial embolism. The main source of emboli is the lipid contents and/or the thrombus on its surface secondary to the rupture of the plaque. These responsible plaques, which can produce emboli and cause embolism symptoms are called "vulnerable plaques" and "dangerous plaque" or "unstable plaque". The main standard of the histological definition of the vulnerable plaque comprises active inflammation, thin fibrous cap and lipid core, large endothelial denudation with surface of platelet aggregation, plaque fissure or injury and severe stenosis. Secondary standard includes surface calcification, yellow shiny patches, intraplaque hemorrhage and positive remodeling. Ultrasound imaging can clearly show the atherosclerotic plaque by technology of two-dimensional imaging, Doppler imaging, elasticity imaging and ultrasound contrast imaging, and provide the size, shape, surface characteristics, internal echo and blood supply information, elastic (hardness) and secondary hemodynamic changes of it. Numerous studies suggested that these sonographic characteristics were associated with the symptoms of the patients. In addition, many studies suggested that there were correlation between these sonographic characteristics and the histological components of the plaques. So we can evaluate the vulnerability of plaque with its sonographic characteristics. Ischemic stroke is the first cause of death and disability in China, of which about 1/3 is caused by carotid atherosclerotic plaque. The therapy of plaque t is an urgent task for the doctors. Rupture of the vulnerable plaque and thrombosis secondary to it is the fundamental reason for atherosclerosis vascular embolism events. Therefore, increasing the stability of plaque is one of the main purpose of the treatment, and is an important index to evaluate the efficacy of various treatment methods. At present, the application of external ultrasonic treatment has opened up a new way for the treatment of plaque, but the evaluation of the effect still is incomprehensive. Only a small amount studies had reported its effect on reducing plaque size, increasing blood flow. This study intends to make further evaluation of its effect on the stabilities of the plaques and its long-term effect on the size of the plaques and the clinical situation, through analyzing the changes of the morphology, surface condition, internal echo, short-term and long term size, and clinical situation before and after the treatment.Subjects and methods68 patients with an-hypo echoic or mixed echoic atherosclerotic plaques in bilateral carotid artery were involved in this study, without using of statins medicine during the treatment of ultrasound.136 plaques (choose the biggest one of each side) divided into two groups, plaques in left side is the treatment group with ultrasound irradiation, while the right side is the control group without treatment. Hitachi EUB 7000 color Doppler ultrasonic diagnostic apparatus and Philips IE33 color Doppler ultrasonic diagnostic apparatus were used for this study. The patients were arranged in the supine position. Their necks were placed on the dedicated cervical orthosis (patent number (China) ZL 2012 2 0244630.X, produced by Luoyang Kangli Medical Instrument Company Ltd.) for detecting carotid plaques and marking the projection of the plaques in the neck skin. The swivel angle of the head and the probe remained unchanged to ensure the accuracy of the ultrasonic testing before and after treatment. Ultrasound diagnosis was conducted by the experienced professional physicians who were unaware of treatment options for patients. Patients were seen by the same physician before and after treatment. The morphology, conditions of the surface and echoes of plaques were observed and recorded. The maximum thickness of each plaque was measured in the longitudinal view. Treatment equipment:LHZ.B-100 ultrasound therapy device for carotid plaques (patent number ZL201120178610.2. 2012-01-18, produced by Luoyang Kangli Medical Device Co., Ltd., China), with an intensity at the surface of the probe 0.75-1 W/cm2 (the estimated energy at the target site is similar to it) a frequency of 800 KHz, and an effective radiation area of 3 cm2. The treatment modality is pulse modulation, the pulse repetition rate is 1Hz (on-off ratio 1:1. that is working for 0.5 seconds and then stopping 0.5 seconds every second.). The beam type is divergent and the duty cycle is 50%.The necks of the patients were placed on the dedicated cervical orthosis at the same angle as before in supine position. The probe of the therapy device was fixed on the skin where it had been marked using a special head frame. Each irradiation was conducted for 30 minutes once a day during 30 days of continuous treatment. Clinical events may be associated with plaque related were recorded 1 year before and after treatment. Examinations, image storing, measurement and recording were conducted before and lday and lyear after treatment. Statistical software SPSS 21.0 was used for all the data analysis. All p-values<0.05 were considered to be statistically significant.Results1. The maximum thickness (T) of plaques:1day and 1year after the end of ultrasound treatment, both T values were decreased compared with those before treatment (P<0.01). The fall of treatment group is larger that of control group, show that the treatment is effective (P=0.01).2. The morphologies of plaques:1 day after the end of treatment, the morphology of 10 out of the 29 irregular plaques in treatment group improved; 19 out of them had no obvious change, the improvement rate of it was of 34.5%. While none out of the 28 irregular plaques in control group was improved.The effect on morphological improvement in treatment group was significantly obvious than that in control group (P<0.01).3. The surface condition of plaques:1 day after the end of treatment, the surfaces of 11 out of the 21 plaques with discontinuous surfaces in treatment group improved; 10 out of them had no obvious change, the improvement rate of it was 52.4%. While none out of the 20 plaques with discontinuous surfaces in control group was improved.The effect on surface condition improvement in treatment group was significantly obvious than that in control group (P<0.01).4. The internal echo of plaques:1 day after the end of treatment, the internal echo of 30 out of the 68 plaques in treatment group increased; 38 out of them had no obvious change, the improvement rate of it was 44.1%. While 8 of the 68 plaques in control group were increased,54 out of them no changes,6 out them decreased, the improvement rate of it was 11.8%. The effect on internal echo improvement in treatment group was significantly obvious than that in control group (P<0.01).5. Clinical setting:1year after the end of the treatment, the number of possible related clinical events decreased in the 12 out of the 20 plaques with possible related clinical events 1year before treatment; 8 out of them no change; the improvement rate was 60%. One new cases of TIA may be related to the plaque of the same side. As to the control group, the number of possible related clinical events decreased in the 6 out of the 21 plaques with possible related clinical events 1year before treatment; 15 out of them no change; the improvement rate was 28.6%. Three new cases of clinical events may be related to the plaque of the same side. The effect on clinical improvement in treatment group was significantly obvious than that in control group (P<0.01).Conclusions1. External ultrasound treatment for carotid atherosclerotic plaques can reduce the maximum thickness of plaque and has long-term effect.2. External ultrasound treatment for carotid atherosclerotic plaques can improve the sonographic characteristics include morphology、surface condition and internal echo, and so suggest that it can increase stability of plaque.3. External ultrasound treatment for carotid atherosclerotic plaques can decrease the occurrence of clinical events, and so suggest that it can improve the vulnerability of plaque.