Renal Nerve Stimulation and Renal Denervation in Patients With Sympathetic Ventricular Arrhythmias

Study Overview
=================
Brief Summary
-----------------
Rationale: Sympathetic activity plays an important role in the pathogenesis of ventricular tachyarrhythmia. Previous studies have shown evidence of significant heritable influences on individual responses to adrenergic stimulation. Catheter-based renal sympathetic denervation (RDN) is a novel treatment option for patients with resistant hypertension, proved to reduce local and whole-body sympathetic activity. The investigators hypothesize that percutaneous transluminal electrical stimulation of the sympathetic nerve bundles in the renal arteries will cause ventricular arrhythmias and renal denervation will suppress these arrhythmias in patients with sympathetic ventricular arrhythmias. Objective: This study will investigate the effects of renal nerve stimulation before and after percutaneous transluminal RDN on cardiac excitable properties including induction of ventricular tachy-arrhythmias before and after RDN in six studies, i.e. patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome and arrhythmogenic right ventricular cardiomyopathy (ARVC), sympathetically driven ventricular arrhythmias, hypertrophic cardiomyopathy (HCM), dilated non-ischemic cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). The aim of the six studies is to assess the anti-arrhythmic effects of RDN in patients with sympathetic ventricular tachy-arrhythmias. Study design: Investigator initiated, multi centre, six pretest-posttest design studies. Study population: Patients with recurrent sympathetically driven ventricular arrhythmia despite optimal pharmacological therapy. Patients should be diagnosed with CPVT and certain types of long QT syndrome, ARVC, HCM, DCM and ICM. Eligible patients will be in the age category of 18-85 year. Intervention: RDN will be performed according to routine clinical practice. Prior to the ablation procedure, catheter mapping of the renal arteries will be performed according to routine clinical practice. Clinical and biological responses to transluminal electrical renal nerve stimulation will be assessed before and after RDN. Study endpoints: Main procedural study endpoint: Induction of ventricular arrhythmias in response to renal nerve stimulation prior to RDN and absence of renal nerves stimulation induced ventricular arrhythmias after RDN. Main clinical study endpoint: Development of ventricular arrhythmia during exercise stress testing performed 6 months after procedure. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: In several studies, it was shown that RDN was safe. The intervention resulted in significantly better control of blood pressure with less medication, and beneficial changes in heart rate variability, autonomic sympathetic balance, renal arteriolar function, and a higher success of atrial fibrillation prevention. In case reports and case series, RDN had a favourable effect in patients with sympathetic drug refractory ventricular tachy-arrhythmias.

Official Title
-----------------
Renal Nerve Stimulation and Renal Denervation in Patients With Sympathetic Ventricular Arrhythmias: an Investigator Initiated Trial

Conditions
-----------------
Arrhythmias, Cardiac

Intervention / Treatment
-----------------
* Procedure: RNS and RDN


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient is willing and able to comply with the protocol and has provided written informed consent. The patient falls within the target group as stated in 4.1. Patient is an acceptable candidate for RDN treatment Patient is 18-85 years of age Documentation of ventricular arrhythmia (ECG, rhythm strip or ICD interrogation) Exclusion Criteria: Contraindication to anticoagulation therapy or heparin. Previous selective cardiac sympathetic denervation or previous RDN procedure. Acute coronary syndrome, cardiac surgery, PCI or stroke within 3 months prior to enrolment. Untreated hypothyroidism or hyperthyroidism. More than grade 1/3 valvular regurgitation and/or significant valve stenosis (moderate or severe). Severe LV dysfunction (LVEF <20% and/or grade 3/4 diastolic dysfunction). Enrolment in another investigational drug or device study. Woman currently pregnant or breastfeeding or not using reliable contraceptive measures during fertile age. Mental or physical inability to participate in the study. Planned cardiovascular intervention. Life expectancy ≤ 12 months. Renal artery stenosis >50% of the arterial lumen, or renal artery lumen ≤3 mm. Complex renal artery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: CPVT<br>catecholaminergic polymorphic ventricular tachycardia (CPVT) patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|
| Other: long QT syndrome<br>long QT syndrome patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|
| Other: ARVC<br>arrhythmogenic right ventricular cardiomyopathy (ARVC) patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|
| Other: HCM<br>hypertrophic cardiomyopathy (HCM) patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|
| Other: DCM<br>dilated non-ischemic cardiomyopathy (DCM) patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|
| Other: ICM<br>ischemic cardiomyopathy (ICM) patients | Procedure: RNS and RDN<br>* The patients will undergo electrical renal nerve stimulation and subsequently renal nerve denervation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction of ventricular arrhythmias (e.g. ventricular tachycardia and ventricular fibrillation) | Induction of ventricular arrhythmias in response to RNS prior to RDN and absence of RNS induced ventricular arrhythmias after RDN | A few minutes before RDN RNS will be performed. Time frame before RDN: 0-10 min. after RNS and before RDN. Time frame after RDN: 0-10 min. | 
| Development of ventricular arrhythmia | Development of ventricular arrhythmia during exercise stress testing performed 6 months after procedure/intervention | 6 months after procedure/intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first detection of ventricular arrhythmia or appropriate ICD therapy | Time to first detection of ventricular arrhythmia or appropriate ICD therapy with the monitoring period starting immediately after the intervention. | procedure/intervention-12 month follow up | 
| Changes in ventricular refractoriness (frequency) | Changes in ventricular refractoriness (frequency, beats/min) to programmed electrical stimulation in the setting of routine electrophysiological study before and directly (0-10 min) after RDN. | procedure/intervention | 
| Changes in ventricular refractoriness (duration) | Changes in ventricular refractoriness (duration, sec) to programmed electrical stimulation in the setting of routine electrophysiological study before and directly (0-10 min) after RDN. | procedure/intervention | 
| Number of ventricular arrhythmias | Inducibility (number) of ventricular arrhythmias to programmed electrical stimulation in the setting of routine electrophysiological study before and after RDN. | procedure/intervention | 
| Ventricular arrhythmia burden | Ventricular arrhythmia burden after 6 and 12 months of follow-up in patients with ICD or continuous rhythm monitoring with a loop recorder. The monitoring period starts immediately after the intervention. | procedure/intervention- 6,12 months follow up | 
| Blood pressure | Blood pressure at 6 and 12 months after the intervention | 6-12 months follow up | 
| Number of (Supra-)Ventricular arrhythmias induced by exercise testing | Number of (Supra-)Ventricular arrhythmias induced by exercise testing | baseline- 6 months follow up | 
| (Supra-)Ventricular arrhythmias response changes (frequency) induced by exercise testing | (Supra-)Ventricular arrhythmias response changes (frequency, beats/min) induced by exercise testing | baseline- 6 months follow up | 
| (Supra-)Ventricular arrhythmias response changes (duration) induced by exercise testing | (Supra-)Ventricular arrhythmias response changes (duration, sec) induced by exercise testing | baseline- 6 months follow up | 
| Changes in heart rate variability | Changes in heart rate variability measures tested by Holter monitoring compared to measurement before the intervention | baseline- 3, 6 and 12 month follow up | 
| Changes in prevalence of events | Changes in prevalence of events (hospital admission for VT or appropriate ICDshock) in the period of one year after intervention compared to a one year period before intervention. | 12 month before procedure/intervention-12 month follow up | 
| Change in blood pressure | Change in blood pressure compared to measurement before the intervention | baseline- 6, 12 month follow up | 
| Heart rate response changes induced by exercise testing | Heart rate response changes induced by exercise testing | baseline- 6 months follow up | 
| Blood pressure response changes induced by exercise testing | Blood pressure response changes induced by exercise testing | baseline-6 months follow up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Denervation, Renal Artery