Alcohol septal ablation for hypertrophic obstructive cardiomyopathy future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Future or investigational therapies

Emerging pharmacologic, interventional, and genetic therapies may alter the future role of alcohol septal ablation (ASA) in obstructive hypertrophic cardiomyopathy (HCM). Approved cardiac myosin inhibitors are discussed here only in relation to their still-investigational potential to defer or replace septal reduction therapy (SRT). Novel septal ablation and gene-based therapies remain investigational and should not be presented as equivalent alternatives to guideline-recommended ASA or surgical myectomy.[1]

Current development landscape

Emerging therapies relevant to the future role of ASA
Therapy Development stage Evidence base Current clinical status
Cardiac myosin inhibitors Mavacamten and aficamten are approved; long-term positioning relative to SRT remains under investigation Randomized trials and extended follow-up Approved within current indications; ability to permanently replace SRT is unproven
Next-generation sarcomere modulators Early phase II development Open-label and early-phase studies Investigational
Percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) Clinical observational development Predominantly single-center cohorts; no randomized comparison with ASA or myectomy Investigational
Endocardial radiofrequency ablation Early clinical development Small case series Investigational
Pulsed field septal ablation First-in-human and preclinical development Case report and porcine studies Investigational
MYBPC3 gene replacement Phase Ib/II Preliminary data from a small initial cohort Clinical-trial use only
Genome editing and RNA silencing Preclinical Murine and other experimental models No established human use

Cardiac myosin inhibitors: evolving role

Mavacamten and aficamten are approved therapies for symptomatic obstructive HCM.[2] Their potential to defer or permanently replace ASA remains under investigation.

Potential to defer septal reduction therapy

In VALOR-HCM, approximately 84% of patients initially referred for SRT remained free of SRT eligibility at 128 weeks while receiving mavacamten, with sustained symptomatic and gradient improvement among patients continuing treatment.[3] It remains unknown whether continued myosin inhibition permanently avoids SRT or delays intervention while therapy is maintained.[4][5]

Ongoing studies are evaluating whether cardiac myosin inhibitors affect atrial fibrillation, heart failure, sudden cardiac death, hypertrophy, fibrosis, and other outcomes beyond symptom and gradient reduction.[5]

Potential first-line use

In MAPLE-HCM, aficamten monotherapy produced greater improvement in peak oxygen uptake than metoprolol monotherapy (between-group difference 2.3 mL/kg/min) and also improved NYHA functional class, health status, Valsalva LVOT gradient, NT-proBNP, and left atrial volume index. A multidomain analysis classified 78% of aficamten recipients and 3% of metoprolol recipients as positive or complete responders.[6]

These findings raise the possibility that cardiac myosin inhibitors may eventually move earlier in the treatment sequence, potentially narrowing referral for ASA. This positioning is not yet established, and the optimal sequence among beta blockers, myosin inhibitors, ASA, and surgical myectomy remains unresolved.[7][1]

Next-generation sarcomere modulators

EDG-7500 is a selective cardiac sarcomere modulator under investigation in the phase II open-label CIRRUS-HCM trial in adults with obstructive or nonobstructive HCM. Its clinical profile relative to mavacamten and aficamten has not been established.[8][9]

Novel percutaneous septal reduction techniques

Novel catheter-based techniques aim to reduce septal mass without dependence on a suitable septal perforator artery. None are included in the 2024 AHA/ACC treatment algorithm, and none have demonstrated superiority or noninferiority to ASA or myectomy in a randomized trial.[1][10]

Percutaneous intramyocardial septal radiofrequency ablation

Percutaneous intramyocardial septal radiofrequency ablation (PIMSRA), also called the Liwen procedure, delivers radiofrequency energy directly into the hypertrophied septum through a percutaneous approach under imaging guidance.

A single-center observational study of 76 patients reported a reduction in median resting LVOT gradient from 70 to 20 mm Hg at a median follow-up of 14 months. NYHA class III or IV decreased from 51% at baseline to 0%. No in-hospital or 30-day death, bundle branch block, or permanent pacemaker implantation was reported.[11]

A small series of 12 patients with residual obstruction after ASA found that PIMSRA was technically feasible; 92% achieved a resting gradient below 50 mm Hg at a median 12-month follow-up, without permanent pacemaker implantation.[12]

Observational comparative evidence suggests that PIMSRA may produce less gradient and septal-thickness reduction than ASA. Its major limitations are the concentration of evidence in a small number of centers, absence of randomized comparisons, and limited long-term durability data.[10][11]

Endocardial septal radiofrequency ablation

Transcatheter endocardial septal radiofrequency ablation delivers energy to the septal endocardial surface, usually through a retrograde aortic approach. Evidence is limited to small series, with uncertain long-term efficacy and smaller gradient reductions than those generally reported after established SRT.[10]

Pulsed field septal ablation

Pulsed field ablation produces nonthermal myocardial injury through irreversible electroporation. Proposed advantages include greater tissue selectivity and less acute edema, but these potential benefits have not been established in comparative clinical studies.

A first-in-human case report described percutaneous endocardial septal pulsed field ablation in drug-refractory obstructive HCM. The LVOT gradient decreased from 73 to 40 mm Hg at 1 month without atrioventricular block.[13]

Preclinical porcine studies demonstrated myocardial injury and regional hypokinesis without significant acute edema, inflammatory infiltration, or conduction disturbance.[14] Pulsed field septal ablation remains at the earliest clinical stage; no comparative or long-term human data are available.

Other emerging approaches

Other early investigational techniques include:

  • Transapical beating-heart septal myectomy
  • Transcatheter septal myotomy
  • Stereotactic septal radioablation
  • Septal scoring along the midline endocardium (SESAME)[10][9]

Published experience with these approaches is insufficient to define patient selection, procedural risk, durability, or comparative effectiveness.

Emerging procedural planning technologies

Three-dimensional image guidance and other advanced imaging strategies are being incorporated into experimental septal ablation procedures to improve lesion targeting and avoid adjacent conduction tissue or coronary structures.[14][10] Whether these approaches improve procedural safety, reproducibility, or clinical outcomes has not been established.

Gene-based therapies

Gene-based therapies aim to treat the underlying sarcomeric defect rather than downstream obstruction. Their potential to prevent or reverse hypertrophy could ultimately reduce the need for SRT, but clinical development remains early and genotype-specific.[15]

AAV9-mediated MYBPC3 replacement

TN-201 is an adeno-associated virus serotype 9 vector carrying MYBPC3. It is under evaluation in the phase Ib/II MyPEAK-1 dose-escalation trial (NCT05836259) in adults with obstructive or nonobstructive HCM and pathogenic MYBPC3 variants.[8][15]

Preliminary findings from the first three treated patients demonstrated cardiac vector transduction, increased MYBPC3 protein expression, stabilization or improvement of reported clinical parameters, and acceptable early tolerability.[8] These findings are proof of concept only and do not establish clinical efficacy, durability, or long-term safety.

Genome editing and RNA silencing

Preclinical gene-editing approaches include:

  • Adenine base editing delivered through dual AAV9 vectors corrected the MYH7 R403Q variant in at least 70% of ventricular cardiomyocytes in mice and prevented development of hypertrophy.[16]
  • A high-precision Cas13d RNA-targeting system selectively suppressed pathogenic MYH7 alleles and prevented hypertrophy in two mouse models.[17]
  • Small interfering RNA strategies targeting altered messenger RNA remain in preclinical development.[4]

No genome-editing or RNA-silencing therapy has established clinical efficacy in humans with HCM. Major unresolved issues include off-target effects, vector-related toxicity and immunogenicity, incomplete tissue delivery, durability, manufacturing, and applicability across the genetically heterogeneous HCM population.[18]

Clinical implications

  1. Do not substitute an investigational septal reduction technique or gene therapy for guideline-recommended ASA or surgical myectomy outside a clinical trial.[1]
  2. Approved cardiac myosin inhibitors may defer SRT, but patients require continued assessment for persistent or recurrent obstruction, symptoms, systolic dysfunction, and treatment intolerance.
  3. Consider referral to a participating research center for patients interested in PIMSRA, pulsed field ablation, or another novel septal intervention; these procedures are not guideline-endorsed alternatives to conventional SRT.
  4. Gene therapy is not available as routine treatment for HCM. Trial eligibility is currently limited to patients with qualifying pathogenic variants and other protocol-specific criteria.
  5. Clearly distinguish early physiological or surrogate outcomes from evidence of durable clinical benefit.

Evidence limitations

  • No novel percutaneous septal technique has been compared with ASA or myectomy in a randomized trial.
  • Most PIMSRA data arise from single-center observational cohorts, limiting generalizability.
  • Human pulsed field septal ablation evidence is limited to a case report.
  • Early TN-201 findings involve only a small initial cohort and do not establish efficacy.
  • Genome-editing and RNA-silencing strategies remain preclinical.
  • The optimal sequencing of cardiac myosin inhibitors and SRT is unresolved.
  • Whether cardiac myosin inhibitors modify fibrosis, arrhythmic risk, heart failure progression, or mortality remains unknown.
  • The 2024 AHA/ACC guideline does not provide recommendations for PIMSRA, pulsed field septal ablation, or gene therapy.[1]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Ommen SR, Ho CY, Asif IM; et al. (2024). "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines". Journal of the American College of Cardiology. 83 (23): 2324–2405. doi:10.1016/j.jacc.2024.02.014.
  2. ↑ "FDA Orange Book". U.S. Food and Drug Administration. Retrieved 2026-08-09.
  3. ↑ Desai MY, Wolski K, Owens A; et al. (2025). "Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results From VALOR-HCM". Circulation. 151 (19): 1378–1390. doi:10.1161/CIRCULATIONAHA.124.072445. PMID 39556124 Check |pmid= value (help).
  4. ↑ 4.0 4.1 Braunwald E (2025). "Hypertrophic Cardiomyopathy". The New England Journal of Medicine. 393 (10): 1004–1015. doi:10.1056/NEJMra2413445.
  5. ↑ 5.0 5.1 Quill S, Amin AS, Asselbergs FW; et al. (2025). "Myosin Inhibitors for Treatment of Hypertrophic Cardiomyopathy". Cochrane Database of Systematic Reviews. 6: CD016183. doi:10.1002/14651858.CD016183.
  6. ↑ Garcia-Pavia P, Maron MS, Masri A; et al. (2025). "Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy". The New England Journal of Medicine. 393 (10): 949–960. doi:10.1056/NEJMoa2504654.
  7. ↑ Grupper A, Sverdlov AL, Cheema BS, Nasrollahizadeh A, Hosseini K (2026). "Evolving Strategies in Obstructive Hypertrophic Cardiomyopathy: Myosin Inhibitors as Monotherapy Compared With Beta-Blockers". Heart Failure Reviews. 31 (1): 38. doi:10.1007/s10741-026-10603-9. PMID 41848906 Check |pmid= value (help).
  8. ↑ 8.0 8.1 8.2 Desai MY, Maurizi N, Biagini E; et al. (2025). "Pathophysiology and Therapeutic Needs in Nonobstructive Hypertrophic Cardiomyopathy". JACC: Heart Failure. 13 (11): 102658. doi:10.1016/j.jchf.2025.102658. PMID 40997544 Check |pmid= value (help).
  9. ↑ 9.0 9.1 Li-Wen Chu E, Seung Kim D, Masri A (2025). "Emerging Pharmacological and Invasive Therapies for Hypertrophic Cardiomyopathy With Obstructive Physiology". Cardiac Failure Review. 11: e27. doi:10.15420/cfr.2025.08. PMID 41234531 Check |pmid= value (help).
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Cui H, Lai Y, Schaff HV (2026). "Septal Reduction Therapies for Obstructive Hypertrophic Cardiomyopathy: Current Strategies and Evolving Innovations". Trends in Cardiovascular Medicine. doi:10.1016/j.tcm.2026.02.004. PMID 41654203 Check |pmid= value (help).
  11. ↑ 11.0 11.1 Xie X, Chen S, Cui Y; et al. (2024). "Midterm Outcomes of Percutaneous Intramyocardial Septal Radiofrequency Ablation for Hypertrophic Cardiomyopathy: A Single-Center, Observational Study". Journal of the American Heart Association. 13 (15): e034080. doi:10.1161/JAHA.123.034080. PMID 39056345 Check |pmid= value (help).
  12. ↑ Zhang J, Hsi DH, Ta S; et al. (2025). "Percutaneous Intramyocardial Septal Radiofrequency Ablation for Hypertrophic Cardiomyopathy With Residual Obstruction After Alcohol Septal Ablation". The Canadian Journal of Cardiology. doi:10.1016/j.cjca.2025.08.355. PMID 41015247 Check |pmid= value (help).
  13. ↑ Tian Y, Zhang H, Yang S; et al. (2026). "Percutaneous Endocardial Septal Pulsed Field Ablation for Hypertrophic Obstructive Cardiomyopathy: A Case Report". Pacing and Clinical Electrophysiology. 49 (3): 308–314. doi:10.1111/pace.70103.
  14. ↑ 14.0 14.1 Chang R, Luo D, He W; et al. (2024). "A Novel Method for Septal Reduction Therapy by Three-Dimensional Guided Transvenous Intraseptal Pulsed-Field Ablation". Heart Rhythm. 21 (3): 258–267. doi:10.1016/j.hrthm.2023.11.020. PMID 38008368 Check |pmid= value (help).
  15. ↑ 15.0 15.1 Argiro A, Bui Q, Hong KN; et al. (2024). "Applications of Gene Therapy in Cardiomyopathies". JACC: Heart Failure. 12 (2): 248–260. doi:10.1016/j.jchf.2023.09.015. PMID 37966402 Check |pmid= value (help).
  16. ↑ Reichart D, Newby GA, Wakimoto H; et al. (2023). "Efficient in Vivo Genome Editing Prevents Hypertrophic Cardiomyopathy in Mice". Nature Medicine. 29 (2): 412–421. doi:10.1038/s41591-022-02190-7. PMID 36797483 Check |pmid= value (help).
  17. ↑ Yang P, Lou Y, Geng Z; et al. (2024). "Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy". Circulation. 150 (4): 283–298. doi:10.1161/CIRCULATIONAHA.123.067890. PMID 38752340 Check |pmid= value (help).
  18. ↑ Agarwal R (2026). "Gene Therapy for Cardiomyopathy: Tools, Targets, and Trials". Circulation: Heart Failure. 19 (7): e013361. doi:10.1161/CIRCHEARTFAILURE.125.013361. PMID 42109120 Check |pmid= value (help).
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