Alcohol septal ablation for hypertrophic obstructive cardiomyopathy historical perspective

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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]

Historical Perspective

Conceptual foundations

The conceptual basis for alcohol septal ablation (ASA) emerged from observations that transient coronary balloon occlusion could suppress regional myocardial contraction and that ethanol injected into a septal perforator could create a controlled myocardial lesion. Brugada and colleagues initially used septal alcohol injection for chemical ablation of ventricular tachycardia, establishing the feasibility of catheter-based ethanol delivery before its application to left ventricular outflow tract (LVOT) obstruction.[1]

At that time, surgical myectomy was the only established invasive treatment for obstructive hypertrophic cardiomyopathy (HCM). Surgical relief of LVOT obstruction had been introduced by Cleland in 1958 and subsequently refined through the transaortic myectomy developed by Morrow. By the 1990s, myectomy was established at specialist centers but required sternotomy and cardiopulmonary bypass, prompting interest in a less invasive septal reduction strategy.[2]

Introduction of alcohol septal ablation

Two groups independently applied catheter-based septal alcohol injection to obstructive HCM in 1994. Gietzen and colleagues presented preliminary experience at the German Cardiac Society meeting in April 1994. Ulrich Sigwart presented his initial procedures in London in June 1994 and published the first peer-reviewed report, describing three patients, in The Lancet in 1995.[1][3][4]

Sigwart's original procedures relied on angiographic identification of the target septal perforator and used an average of approximately 4.5 mL of absolute ethanol without myocardial contrast echocardiographic guidance. The resulting immediate and sustained reduction in LVOT gradient established the feasibility of percutaneous septal reduction, but the relatively large and imprecisely localized infarctions contributed to early safety concerns.[1][3]

Early adoption and controversy

Following the 1995 publication, ASA was adopted rapidly in Germany and other European countries and subsequently in North America. Avoidance of sternotomy and cardiopulmonary bypass, together with shorter recovery, made the procedure particularly attractive for older patients and those considered at increased surgical risk.[5][2]

Early experience was nevertheless characterized by substantial variability in technique and outcomes. Reported concerns included:

  • Complete atrioventricular block requiring permanent pacing; observational estimates for abnormal atrioventricular conduction after ASA ranged from 10% to 33%, while a meta-analysis of observational studies estimated permanent pacing in 10% after ASA compared with 4.4% after myectomy. Transient atrioventricular block occurred in approximately 15%–50% and usually resolved within 24 hours, accounting for some of the higher figures reported in early series.[6]
  • Large or inaccurately targeted septal infarctions and occasional ventricular septal defect.
  • Incomplete or nonuniform gradient reduction compared with myectomy.
  • Potential ventricular proarrhythmia from the iatrogenic septal scar.
  • Performance at low-volume centers without multidisciplinary HCM expertise.[7][8]

The magnitude of the pacing difference between ASA and myectomy has not been consistent across data sources. An analysis of the National Inpatient Sample found similar permanent-pacemaker requirements of approximately 9%–14% for both procedures. Right bundle branch block develops in approximately 60% of patients after ASA, whereas up to 90% develop left bundle branch block after myectomy.[6]

A persistent anatomic boundary also shaped the historical division of roles between ASA and myectomy. ASA has been less effective in patients with resting gradients ≥100 mm Hg or septal thickness ≥30 mm and has been associated with a greater need for repeat intervention for residual obstruction. Observational comparisons have reported similar 5-year survival but lower 10-year survival after ASA.[9]

The 2004 review by Nishimura and Holmes additionally emphasized that up to 20% of evaluated patients lacked a septal perforator supplying the critical obstructive septal territory.[7]

Evolution of technique

The introduction of myocardial contrast echocardiography (MCE) during the late 1990s was the most important technical advance in ASA. Contrast injection into a candidate septal perforator allowed operators to confirm its myocardial perfusion territory before ethanol delivery.[1][10]

Period Technical approach Historical significance
Early experience Angiographic target-vessel selection without MCE; average ethanol volume approximately 4.5 mL Demonstrated feasibility but produced relatively large, less predictable infarctions and high rates of conduction injury.[1]
Late 1990s onward MCE-guided target selection; MCE changed the target vessel or prompted procedure abandonment in approximately 15%–20% of cases Improved anatomic precision and reduced injury to nontarget myocardium.[1][10]
Contemporary evolution Progressive reduction of ethanol volume to approximately 1–3 mL in most procedures Produced smaller, targeted infarctions while reducing permanent-pacemaker rates to approximately 7%–20% across contemporary series, with recent syntheses citing approximately 10%.[11][12]

These refinements, together with more restrictive patient selection and increasing operator experience, transformed ASA from a relatively imprecise alcohol-induced infarction into an imaging-guided septal reduction procedure.

Age emerged as an important determinant of conduction injury. In a Euro-ASA analysis, permanent-pacemaker implantation within 30 days increased from approximately 6%–7% among patients aged ≤60 years to approximately 12% at 61–70 years and nearly 20% among patients older than 80 years. The enrichment of early ASA cohorts with older, higher-surgical-risk patients partly explains their elevated pacing rates.[11]

Maturation of the evidence base

No randomized trial has directly compared ASA with surgical myectomy. Acceptance of ASA therefore developed through single-center experience, national cohorts, systematic reviews, and multinational registries.[8]

The North American ASA Registry included 875 patients treated at nine institutions in the United States and Canada, with a mean follow-up of 2.1 years. Reported survival was 97%, 86%, and 74% at 1, 5, and 9 years, respectively. More effective ablation, reflected by smaller post-ablation septal thickness and no requirement for repeat treatment, was associated with lower mortality.[13]

The registry investigators also noted that rates of life-threatening ventricular arrhythmia exceeded those reported in contemporaneous myectomy series and that the post-ablation LVOT gradient was higher than in surgical cohorts. This difference was attributed to the dependence of ASA on successful cannulation of the artery supplying the culprit septal segment, whereas myectomy produces direct mechanical relief.[13]

The high-volume Bad Nauheim experience demonstrated that ASA could be performed with low procedural mortality in an expert single-operator program and reinforced the association between procedural volume and outcomes.[14]

The Euro-ASA Registry subsequently enrolled 1,275 patients across European centers and established multicenter evidence for sustained gradient and functional improvement during long-term follow-up.[15] Its reported 10-year survival of 77% was identical to the 10-year survival reported in a Mayo Clinic cohort of 749 patients undergoing myectomy, a historically important observation in the subsequent debate over the relative position of ASA and surgery.[1]

The 2024 SHaRE Registry analysis, drawn from 13 high-volume international HCM centers, included 10,225 patients with HCM, of whom 1,832 (18%) underwent septal reduction therapy: 1,377 (75%) underwent myectomy and 455 (25%) underwent ASA. Median follow-up was 6.8 years (range 3.4–9.8 years; 12,565 person-years), and 30-day mortality after septal reduction therapy was 0.4% (8 of 1,832). During follow-up, HCM-related death occurred in 4% (0.6% per year), the heart-failure composite in 13% (1.9% per year), and the ventricular-arrhythmia composite in 5% (0.7% per year). Reported 10-year event-free survival was 83%, and de novo atrial fibrillation developed in 21%.[16]

Extended follow-up has partially addressed the long-standing concern regarding the iatrogenic septal scar. In a cohort followed for up to 25 years after ASA, freedom from HCM-related death was approximately 86% at 10 years compared with 73% all-cause survival. Most deaths were therefore noncardiac or unrelated to HCM, while sudden cardiac death remained uncommon.[17]

Evolution of guideline recommendations

Guideline era Historical position of ASA
2003 ACC/AHA Recognized ASA as an alternative to myectomy but limited its role primarily to patients who were not suitable surgical candidates.[1][18]
2011 ACCF/AHA Designated ASA a Class IIa option for patients with a contraindication to surgery or unacceptable surgical risk and emphasized performance at experienced centers.[3][18]
2014 ESC Accepted ASA as an alternative to myectomy in selected patients when performed by experienced operators and was less restrictive than contemporaneous US guidance regarding patients who remained potential surgical candidates. Readers should consult the primary 2014 ESC document for the formal class of recommendation and level of evidence.[1]
2020 AHA/ACC Gave septal reduction therapy at experienced centers a Class 1 recommendation and included a specific Class 1 recommendation for ASA when surgery was contraindicated or carried unacceptable risk. The broader septal reduction therapy recommendation carried level of evidence B-NR, whereas the ASA-specific recommendation for high surgical risk carried level of evidence C-LD—a distinction retained in the 2024 guideline.[18][9]
2023 ESC Retained ASA as an acceptable septal reduction option for selected patients at experienced centers.[18]
2024 AHA/ACC multisociety Preserved the Class 1 framework for septal reduction therapy and the specific high-surgical-risk indication for ASA. The guideline also incorporated cardiac myosin inhibition as a Class 1 medical escalation strategy, changing the treatment pathway preceding invasive septal reduction.[9][19]

The cardiac myosin inhibitor era

The approval of mavacamten in 2022 introduced the first noninvasive therapy capable of substantially reducing the proportion of already-referred patients who remained eligible for septal reduction. VALOR-HCM therefore marked an important change in the historical pathway from drug-refractory symptoms directly to myectomy or ASA.[20]

Aficamten (MYQORZO), a next-generation cardiac myosin inhibitor supported by the phase 3 SEQUOIA-HCM trial, was approved in the United States and China in December 2025 and in the European Union in February 2026, further expanding the medical alternatives preceding septal reduction.[21][22]

Thirty-year perspective

The transition from high-dose, angiography-only alcohol injection to low-dose, MCE-guided ablation is essential when interpreting the historical literature because complication rates from the pre-MCE era are not directly comparable with contemporary practice.

Thirty years after Sigwart's first procedures, ASA is established as a standard catheter-based option that reduces the LVOT pressure gradient by approximately 70%–80%, leaves a residual gradient >30 mm Hg in approximately 10%–20% of patients, and carries procedural mortality below 1%. Approximately 10% of patients require permanent pacing for high-grade atrioventricular block. These outcomes remain contingent on appropriate selection and performance at centers with comprehensive HCM expertise, including access to surgical myectomy.[12]

The historical record also leaves several unresolved limitations: no randomized comparison with myectomy has been performed, observational comparisons remain vulnerable to selection bias, and outcomes have consistently depended on institutional and operator experience. The volume–outcome relationship should therefore be understood as a historical legacy of early variable adoption as well as a contemporary quality requirement.[8][14][9]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Liebregts M, Vriesendorp PA, Ten Berg JM (2017). "Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: A Word of Endorsement". Journal of the American College of Cardiology. 70 (4): 481–488. doi:10.1016/j.jacc.2017.02.080.
  2. ↑ 2.0 2.1 Nishimura RA, Seggewiss H, Schaff HV (2017). "Hypertrophic Obstructive Cardiomyopathy: Surgical Myectomy and Septal Ablation". Circulation Research. 121 (7): 771–783. doi:10.1161/CIRCRESAHA.116.309348.
  3. ↑ 3.0 3.1 3.2 Fifer MA, Sigwart U (2011). "Controversies in Cardiovascular Medicine. Hypertrophic Obstructive Cardiomyopathy: Alcohol Septal Ablation". European Heart Journal. 32 (9): 1059–1064. doi:10.1093/eurheartj/ehr013.
  4. ↑ Sigwart U (1995). "Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy". The Lancet. 346 (8969): 211–214. doi:10.1016/S0140-6736(95)91267-3. PMID 7616800.
  5. ↑ Pelliccia F, Niccoli G, Gragnano F; et al. (2019). "Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: A Contemporary Reappraisal". EuroIntervention. 15 (5): 411–417. doi:10.4244/EIJ-D-18-00959.
  6. ↑ 6.0 6.1 Kusumoto FM, Schoenfeld MH, Barrett C; et al. (2019). "2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay". Heart Rhythm. 16 (9): e128–e226. doi:10.1016/j.hrthm.2018.10.037.
  7. ↑ 7.0 7.1 Nishimura RA, Holmes DR (2004). "Hypertrophic Obstructive Cardiomyopathy". The New England Journal of Medicine. 350 (13): 1320–1327. doi:10.1056/NEJMcp030779.
  8. ↑ 8.0 8.1 8.2 Sorajja P (2017). "Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: A Word of Balance". Journal of the American College of Cardiology. 70 (4): 489–494. doi:10.1016/j.jacc.2017.06.011.
  9. ↑ 9.0 9.1 9.2 9.3 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.
  10. ↑ 10.0 10.1 Nagueh SF, Phelan D, Abraham T; et al. (2022). "Recommendations for Multimodality Cardiovascular Imaging of Patients With Hypertrophic Cardiomyopathy: An Update From the American Society of Echocardiography, in Collaboration With the American Society of Nuclear Cardiology, the Society for Cardiovascular Magnetic Resonance, and the Society of Cardiovascular Computed Tomography". Journal of the American Society of Echocardiography. 35 (6): 533–569. doi:10.1016/j.echo.2022.03.012.
  11. ↑ 11.0 11.1 Veselka J, Liebregts M, Cooper R; et al. (2022). "Outcomes of Patients With Hypertrophic Obstructive Cardiomyopathy and Pacemaker Implanted After Alcohol Septal Ablation". JACC: Cardiovascular Interventions. 15 (19): 1910–1917. doi:10.1016/j.jcin.2022.06.034.
  12. ↑ 12.0 12.1 Veselka J (2024). "Looking Back at 30 Years of Alcohol Septal Ablation and Looking Forward to the Future". The Canadian Journal of Cardiology. 40 (5). PMID 37774969 Check |pmid= value (help).
  13. ↑ 13.0 13.1 Nagueh SF, Groves BM, Schwartz L; et al. (2011). "Alcohol Septal Ablation for the Treatment of Hypertrophic Obstructive Cardiomyopathy: A Multicenter North American Registry". Journal of the American College of Cardiology. 58 (22): 2322–2328. doi:10.1016/j.jacc.2011.06.073.
  14. ↑ 14.0 14.1 Batzner A, Pfeiffer B, Neugebauer A; et al. (2018). "Survival After Alcohol Septal Ablation in Patients With Hypertrophic Obstructive Cardiomyopathy". Journal of the American College of Cardiology. 72 (24): 3087–3094. doi:10.1016/j.jacc.2018.09.064.
  15. ↑ Veselka J, Jensen MK, Liebregts M; et al. (2016). "Long-Term Clinical Outcome After Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: Results From the Euro-ASA Registry". European Heart Journal. 37 (19): 1517–1523. doi:10.1093/eurheartj/ehv693.
  16. ↑ Maurizi N, Antiochos P, Owens A; et al. (2024). "Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHaRE Registry". Circulation. 150 (17): 1377–1390. doi:10.1161/CIRCULATIONAHA.124.069378.
  17. ↑ Veselka J, Tesar D, Topalo R, Hansvenclova E, Adlova R (2023). "Follow-Up of Up to 25 Years After Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy". JACC: Cardiovascular Interventions. 16 (12): 1556–1557. doi:10.1016/j.jcin.2023.03.049.
  18. ↑ 18.0 18.1 18.2 18.3 Bali AD, Malik A, Naidu SS (2024). "Treatment Strategies for Hypertrophic Cardiomyopathy: Alcohol Septal Ablation and Procedural Step-by-Step Technique". The American Journal of Cardiology. 212S: S42–S52. doi:10.1016/j.amjcard.2023.10.064.
  19. ↑ Coylewright M, Cibotti-Sun M, Moore MM (2024). "2024 Hypertrophic Cardiomyopathy Guideline-at-a-Glance". Journal of the American College of Cardiology. 83 (23): 2406–2410. doi:10.1016/j.jacc.2024.04.002.
  20. ↑ Braunwald E (2025). "Hypertrophic Cardiomyopathy". The New England Journal of Medicine. 393 (10): 1004–1015. doi:10.1056/NEJMra2413445.
  21. ↑ Shirley M (2026). "Aficamten: First Approval". Drugs. PMID 41941083 Check |pmid= value (help).
  22. ↑ U.S. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Myqorzo (aficamten); approval date December 19, 2025.
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