Renal Denervation in Hypertrophic Cardiomyopathy

Study Overview
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Brief Summary
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Hypertrophic cardiomyopathy (HCM) is the most common inherited monogenic heart disease. There is an abnormal increase in myocardial mass in this disorder that leads to a state of cardiac sympathetic hypertonia, which is involved in disease progression, development of arrhythmias and heart failure. Cardiac sympathetic hyperactivity may constitute a new therapeutic target in HCM patients who persist symptomatic despite conventional treatment. The hypothesis of this project is that renal denervation (a minimally invasive percutaneous interventional therapy with proven efficacy in resistant arterial hypertension) reduces cardiac sympathetic activity in HCM. The SNYPER pilot study is a non-randomized clinical trial with medical devices (proof of concept), in which a renal denervation procedure will be performed in 20 patients with genetically confirmed sarcomeric HCM, severe left ventricular hypertrophy and persistent symptoms. The impact of denervation in reducing the 123I-meta iodo benzyl guanidine (MIBG) washout rate quantified by isotopic tracing (planar imaging and SPECT) at 6 months is established as a primary efficacy objective, and the proportion of renal denervation-related complications as a safety objective. The most relevant secondary endpoints are the outcomes of renal denervation on left ventricular mass (echocardiogram), diastolic function, maximum oxygen consumption (ergospirometer), ventricular arrhythmia burden (Holter), blood pressure (ABPM), N-terminal (NT) Pro Brain Natriuretic Peptide (BNP) and quality of life (KCCQ questionnaire). The results of this study may open the development of a new, technically simple and easily accessible therapeutic line for the treatment of HCM.

Detailed Description
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According to current literature, approximately two-thirds of patients with HCM have persistent symptoms despite conventional treatment. For this reason, novel nonpharmacological therapies such as cardiac resynchronization, endocardial catheter ablation of the interventricular septum or needle-based septal ablation have been proposed, however, none of them having been generalized up to date. Besides, these novel therapies cannot be applied in non-obstructive HCM. The abnormal activation of the sympathetic system represents a relevant mechanism in he pathophysiology of HCM, since it may have implications in the progression and prognosis of the disease. The modulation of the cardiac sympathetic tone by renal denervation could be developed as a new therapeutic target for patients with persistent symptoms despite conventional treatment. The SNYPER pilot study is a prospective, single-center, single-arm, pilot study, evaluating renal denervation in patients with sarcomeric HCM and persistent symptoms despite optimal therapy, over a follow-up period of 6 months. It represents a proof of concept that will quantify the degree in which renal denervation modulates cardiac sympathetic activity in HCM, thus opening a new research line: a non-pharmacological, minimally invasive and safe treatment with potential positive impact on health and well-being of patients with HCM. This is a non-commercial, investigator-driven clinical study funded through a public competitive call by Health Institute Carlos III, Spanish Ministry of Economy (PI21/00480). The study is coordinated by the main investigator from University Hospital 12 de Octubre in Madrid. Several responsibilities are delegated to the Clinical Research Unit (University Hospital 12 de Octubre, Madrid, Spain). The study was planned according to the Good Clinical Practices. SNYPER Pilot Study has been approved by the Ethics Committee and Spanish Health Authorities. All participating patients must give written informed consent before any study procedure occur.

Official Title
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Cardiac Sympathetic Neuromodulation by Renal Denervation in Hypertrophic Cardiomyopathy (SNYPER Pilot Study)

Conditions
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Hypertrophic Cardiomyopathy

Intervention / Treatment
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* Device: Symplicity Spyral multi-electrode renal denervation catheter and Symplicity G3 generator (Renal Denervation System)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sarcomeric HCM (absence of metabolic, syndromic or neurological diseases with increased left ventricular thickness) confirmed by genetic study (pathogenic or probably pathogenic variant identified in a sarcomeric gene). NYHA Class II-IV despite optimal therapy for the last 30 days. Left ventricular septum > 16 mm. Age between 18 and 80 years. Not candidate to septal reduction therapy or valve surgery. Exclusion Criteria: Non sarcomeric causes of increased left ventricular thickness. Left ventricular systolic disfunction (EF < 50%) or dilatation (indexed left ventricular end diastolic volume [LVEDV] > 75 ml/m2 for men and > 62 ml/m2 for women). Blood pressure < 100/50 mmHg. Severe functional impairment due to concomitant diseases. Renal glomerular filtration < 30 ml/min/m2 (Cockcroft-Gault´s formula). Hospitalization for heart failure, stroke or acute coronary syndrome (ACS) in the last 30 days. Heart failure requiring inotropic drugs or intravenous diuretics over the last 30 days, or in the waiting list for heart transplantation. Unfavorable renal artery anatomy (significant stenosis, diameter < 2mm, length < 4mm) Women on pregnancy, lactation or fertile age without contraception. Parkinson´s disease or Lewy body dementia. Life expectancy less than one year Unwilling to sign informed consent or to undergo study procedure and visits. Participation in other clinical trial over the last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: renal denervation<br>Renal denervation shall be performed by echo-guided catheterization of the femoral artery, and subsequent cannulation of the renal arteries with a guide catheter. A renal denervation catheter shall be advanced through the guide catheter to the distal portion of the artery. The procedures shall be aimed to deliver as many radiofrequency applications as possible, 0.5 cm apart, intended duration of 60 sec, to all four quadrants of the renal arteries and main branch vessels with > 3 mm diameter. | Device: Symplicity Spyral multi-electrode renal denervation catheter and Symplicity G3 generator (Renal Denervation System)<br>* Minimally invasive percutaneous interventional therapy aimed to modulate the sympathetic nervous system through endovascular ablation of both renal arteries<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac sympathetic nerve activity (123I-MIBG washout rate) | 123I-MIBG washout rate measured by scintigraphy | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional status | New York Heart Association (NYHA) class. From I to IV (higher scores mean a worse outcome) | 6 months | 
| Left ventricular mass | Left ventricular mass assessed by echocardiography (Devereux´s formula, septal and posterior wall thickness) | 6 months | 
| Diastolic function | E / A ratio, deceleration time, E' septal and lateral velocity, E/E´ septal ratio, propagation velocity assessed by echocardiography | 6 months | 
| Subaortic gradient (left ventricular outflow tract obstruction [LVOT]) | Baseline peak LVOT gradient, peak LVOT gradient during Valsalva in millimeters of mercury | 6 months | 
| Number of ventricular tachycardia episodes | Non-sustained ventricular tachycardias episodes recorded by a cardiac electronic implantable device (pacemaker or defibrillator, if previously implanted) | 6 months | 
| Heart rate variability | Number of atrial premature complexes and number of non-sustained atrial tachycardias recorded by 24-hour Holter | 6 months | 
| Maximum oxygen consumption | Maximum oxygen consumption assessed by ergospirometer | 6 months | 
| Blood pressure | Mean, daily and nocturnal systolic and diastolic blood pressure assessed by 24-hour ambulatory monitoring of blood pressure (AMBP) | 6 months | 
| NT-Pro-BNP | Serum NT-Pro-BNP levels | 6 months | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) score | Self-administered health-related quality of life questionnaire composed by 23 items, which provides a score range from 0 to 100. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal denervation