Clinical trial NCT06116357: The Safety and Efficacy of Carotid Body Modulation Therapy in Hypertensive Patients by External Ultrasonic Micro-bubble
Official title: The Safety and Efficacy of Carotid Body Modulation Therapy in Hypertensive Patients by External Ultrasonic Micro-bubble
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Primary Hypertension
Keywords: Carotid body modulation therapy
Hypertension
Carotid body activity
Carotid body volume
Ultrasonic micro-bubble
Lead sponsor: The Second Affiliated Hospital of Chongqing Medical University
Sponsor class: OTHER
Collaborators: name: The Second Affiliated Hospital of Chongqing Medical University
First posted: 2023-11-03
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: primary hypertensive patients
Primary purpose: TREATMENT

Brief summary: The investigators intend to find a noninvasive method for CB modulation therapy and find a simple and convenient indicator for assessing CB activity. This study was designed to evaluate the safety and efficacy of carotid body modulation therapy in hypertensive patients by external ultrasonic micro-bubble and also identify the association between CB volume and CB activity.

Detailed description: Carotid body (CB) hyperactivity, with excessive afferent discharge signal to the respiratory centre anautonomic sympathetic nuclei, can result in hyperventilation and sympathetic hyperactivity. And previous studies have found that CB hyperactivity was common in several kinds of cardiovascular diseases and the investigators also found that CB was obviously enlargement in hypertension and other cardiovascular diseases. Hence, CB might play an important role in the development of these cardiovascular diseases. Moreover, Resection of CB or blockade of P2X3 receptors in CB significantly reduced blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in patients with hypertension. Therefore, CB may be a promising therapeutic target for hypertension. However, the following questions about CB are needed to be addressed urgently. First, the CB volume enlargement may be a promising indicator for selection appropriate patients for CB modulation therapy, but its relationship with the CB hyperactivity is still unclear. Second, although CB resection could significantly reduce BP in hypertensive patients, but the invasive therapy and completely resection may result in severe adverse events.

Based on the aforementioned questions, to find a simple and convenient indicator for assessing CB activity and find a noninvasive method for CB modulation therapy, the investigators designed this study to identify the association between CB volume and CB activity in hypertensive patients and also evaluated the safety and efficacy of carotid body modulation therapy in hypertensive patients by external ultrasonic micro-bubble.

Eligibility criteria: Inclusion Criteria:

* Hypertensive patients for CB modulation therapy

  1. Two or more antihypertensive medications that had been prescribed at least 50% of the manufacturer's maximum dose for at least 2 consecutive weeks before study; Patients take an angiotensin-converting enzyme inhibitor (ACEI) (or angiotensin-ⅱ receptor antagonist (ARB)) and calcium channel blocker (CCB) (or thiazide diuretic) ; Office systolic blood pressure (SBP)≥150 mmHg and \<180mmHg.

     2.24-hour ambulatory systolic blood pressure: ≥135 mmHg and \<170 mmHg

  3.A history of primary hypertension was recorded. 4.Patients who can understand the purpose of the trial, voluntarily participate and sign informed consent, and are willing to cooperate with clinical follow-up
* Patients for CB Volume and activity evaluation Hypertension group

  1. Primary hypertension patients agrees to take part in this study and perform CB MRI, ultrasound, CB activity tests and sign the informed consent.
  2. The office blood pressure of patients ≥ 140/90 mmHg; the patents were diagnosed hypertension and are taking anti-hypertensive drugs could also include, although the office blood pressure \< 140/90 mmHg.
  3. The CB could be detected by carotid ultrasound or MRI. Control group

  <!-- -->

  1. The volunteers agree to take part in this study and perform CB MRI, ultrasound, CB activity tests and sign the informed consent.
  2. The volunteers are healthy.

Exclusion Criteria:

* Hypertensive patients for CB modulation therapy

  1. Carotid body anatomy is not eligible for treatment: ultrasound examination before treatment fail to find carotid body at carotid artery bifurcation.
  2. Carotid body anatomical heterotopic is difficult to select or unsuitable for ultrasound irradiation.
  3. Carotid anatomy that does not meet treatment conditions: severe carotid stenosis or occlusion.
  4. Carotid ulcer.
  5. Severe tortuosity of carotid artery
  6. After carotid artery stenting or stripping
  7. Other conditions that are not suitable for carotid intervention
  8. Glomerular filtration rate (eGFR) \<45 mL/min / 1.73 m2
  9. Have type 1 diabetes or poorly controlled type 2 diabetes (defined as plasma HbA1c≥ 9.0% or 24-hour urinary protein quantity \>1g/24h or proliferative retinal lesions)
  10. postural hypotension.
  11. Recent vascular events: Experienced acute myocardial infarction, unstable angina, syncope, or cerebrovascular accident within 3 months of the screening period.
  12. Suspected secondary hypertension.
  13. Respiratory support: The individual requires long-term oxygen support or mechanical ventilation (except for nighttime breathing support only because of sleep apnea).
  14. Life expectancy \<1 year.
  15. A woman who is pregnant, breastfeeding, or planning to become pregnant.
  16. Subjects who are currently enrolled in another clinical trial and have not completed the primary endpoint.
  17. Allergic to contrast media.
  18. The investigators judged the patients' poor compliance and other reasons for not being suitable for participants in the trial.
  19. Any other conditions that the investigator did not consider appropriate to participate in the trial.
* Patients for CB Volume and activity evaluation

  1. the CB could not be detected by carotid ultrasound or MRI.
  2. The patients have secondary hypertension, heart failure.
  3. The patients have type 1diabetes mellitus, CB tumor.
  4. The patients were diagnosed as OSAS.
  5. The patients have severe chronic constructive pulmonary disease, interstitial lung disease or other severe lung diseases.
  6. Women who are pregnant, breastfeeding, or planning to become pregnant.
  7. Patients with other conditions which are not appropriate for enrollment judged by the investigators.

Primary outcomes:
measure: The change from baseline 24-hour mean ambulatory SBP at 6 months
timeFrame: 6 months
measure: The change from baseline daytime mean ambulatory SBP at 6 months
timeFrame: 6 months
measure: The control rate of hypertension at 6 month
timeFrame: 6 months
Secondary outcomes:
measure: The change from baseline CB activity at 6months
timeFrame: 6 months
measure: The change from baseline CB volume at 6months
timeFrame: 6 months
measure: The change from baseline 24-hour mean ambulatory DBP at 6 months
timeFrame: 6 months
measure: The change from baselines office SBP and DBP at 6 months
timeFrame: 6 months
measure: The incidence of CB modulation therapy associated adverse events including MACE events, hypotension, carotid artery stenosis and hyoxemia at 6 months
timeFrame: 6 months
measure: The differences of CB volume between healthy volunteers and hypertension patients
timeFrame: at baseline
measure: The differences of CB activity between healthy volunteers and hypertension patients
timeFrame: at baseline
measure: The correlation analysis of heart rate variability and CB activity in hypertension patients at baseline
timeFrame: at baseline
Other outcomes:
Locations:
city: Chongqing
country: China
facility: The Second Affilated Hospital of Chongqing Medical Universty
state: Chongqing
Study officials:
affiliation: The Second Affiliated Hospital of Chongqing Medcial University
name: Jing Huang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Xue Q, Wang R, Wang L, Xiong B, Li L, Qian J, Hao L, Wang Z, Liu D, Deng C, Rong S, Yao Y, Jiang Y, Zhu Q, Huang J. Downregulating the P2X3 receptor in the carotid body to reduce blood pressure via acoustic gene delivery in canines. Transl Res. 2021 Jan;227:30-41. doi: 10.1016/j.trsl.2020.06.005. Epub 2020 Jun 14.
citation: Del Rio R, Marcus NJ, Schultz HD. Carotid chemoreceptor ablation improves survival in heart failure: rescuing autonomic control of cardiorespiratory function. J Am Coll Cardiol. 2013 Dec 24;62(25):2422-2430. doi: 10.1016/j.jacc.2013.07.079. Epub 2013 Sep 4.
citation: Iturriaga R, Del Rio R, Idiaquez J, Somers VK. Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease. Biol Res. 2016 Feb 26;49:13. doi: 10.1186/s40659-016-0073-8.
citation: Niewinski P, Janczak D, Rucinski A, Tubek S, Engelman ZJ, Piesiak P, Jazwiec P, Banasiak W, Fudim M, Sobotka PA, Javaheri S, Hart EC, Paton JF, Ponikowski P. Carotid body resection for sympathetic modulation in systolic heart failure: results from first-in-man study. Eur J Heart Fail. 2017 Mar;19(3):391-400. doi: 10.1002/ejhf.641. Epub 2016 Sep 20.
citation: Tan J, Xiong B, Zhu Y, Yao Y, Qian J, Rong S, Yang G, Zhu Q, Jiang Y, Zhou Q, Liu D, Deng C, Ran H, Wang Z, He T, Huang J. Carotid body enlargement in hypertension and other comorbidities evaluated by ultrasonography. J Hypertens. 2019 Jul;37(7):1455-1462. doi: 10.1097/HJH.0000000000002068.