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.

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.

Inclusion Criteria:

1. 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).
2. NYHA Class II-IV despite optimal therapy for the last 30 days.
3. Left ventricular septum > 16 mm.
4. Age between 18 and 80 years.
5. Not candidate to septal reduction therapy or valve surgery.

Exclusion Criteria:

1. Non sarcomeric causes of increased left ventricular thickness.
2. 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).
3. Blood pressure < 100/50 mmHg.
4. Severe functional impairment due to concomitant diseases.
5. Renal glomerular filtration < 30 ml/min/m2 (Cockcroft-Gault´s formula).
6. Hospitalization for heart failure, stroke or acute coronary syndrome (ACS) in the last 30 days.
7. Heart failure requiring inotropic drugs or intravenous diuretics over the last 30 days, or in the waiting list for heart transplantation.
8. Unfavorable renal artery anatomy (significant stenosis, diameter < 2mm, length < 4mm)
9. Women on pregnancy, lactation or fertile age without contraception.
10. Parkinson´s disease or Lewy body dementia.
11. Life expectancy less than one year
12. Unwilling to sign informed consent or to undergo study procedure and visits.
13. Participation in other clinical trial over the last 30 days.

10 milliliters (mL) of total blood, 5mL of serum and 10mL of blood with a commercial formula for RNA preservation shall be collected and stored for future proteomic and genetic analysis.

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