Atrial Fibrillation Substrate and Catheter Ablation Outcomes in MYBPC3 and MYH7-Mediated Hypertrophic Cardiomyopathy

Authors, Journal, Affiliations, Type, DOI

• Authors: Ikram U. Haq, Nadia Akhiyat, Nader Al-Shakarchi, Konstantinos C. Siontis, Siva K. Mulpuru, Alan Sugrue, John Giudicessi, Paul A. Friedman, Samuel J. Asirvatham, Ammar M. Killu
• Journal: JACC: Clinical Electrophysiology, Vol. 10, No. 7, July 2024 (pp. 1380–1391)
• Affiliation: Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
• Type: Original research — retrospective, single-center observational study
• DOI: https://doi.org/10.1016/j.jacep.2024.03.026

Overview

This single-center retrospective study compared left atrial (LA) substrate and catheter ablation outcomes for atrial fibrillation (AF) in 12 patients with pathogenic MYBPC3 or MYH7 variants (gene-positive HCM) versus 15 HCM patients without disease-causing genetic variants (controls). Gene-positive patients had significantly more LA fibrosis detected by high-density electroanatomical mapping (12.3% abnormal voltage vs. 5.7% in controls), despite similar LA pressures — supporting the hypothesis that sarcomeric gene variants promote AF through primary atrial myopathy rather than hemodynamic effects alone. Freedom from AF at 12 months was similar (~75% both groups), but gene-positive patients required significantly more ablation procedures and remained on antiarrhythmic drugs more often.

Keywords

Hypertrophic cardiomyopathy, atrial fibrillation, catheter ablation, MYBPC3, MYH7, electroanatomical mapping, atrial fibrosis, pulmonary vein isolation, voltage mapping, atrial myopathy

Key Takeaways

Background and Rationale

• HCM is the most common inherited cardiomyopathy; MYBPC3 and MYH7 variants are the two most common causative genes
• AF is the most prevalent sustained arrhythmia in HCM; it markedly increases stroke, heart failure, and mortality risk
• Catheter ablation has lower success rates in HCM than the general population and often requires repeat procedures and ongoing antiarrhythmic drugs (AADs)
• Patients with MYH7 variants specifically have higher AF incidence and more atrial/ventricular structural abnormalities
• The effect of specific MYBPC3 or MYH7 variants on atrial myopathy and ablation outcomes was poorly characterized prior to this study

Methods

• Retrospective review of all HCM patients who underwent genetic testing AND AF catheter ablation at Mayo Clinic (January 2014 – December 2022)
• Gene-positive cohort: ACMG-adjudicated pathogenic or likely pathogenic variants in MYBPC3 or MYH7 (n=12: 6 MYBPC3, 6 MYH7)
• Control cohort: HCM patients who tested negative for any disease-causative P/LP variant (n=15)
• High-density electroanatomical mapping (PentaRay catheter, CARTO system) performed in all patients; LA divided into 6 segments: posterior, roof, anterior, lateral, inferior, septal
• Voltage thresholds: dense scar <0.1 mV; intermediate scar 0.1–0.5 mV; normal >0.5 mV
• All patients underwent PVI as primary endpoint; additional substrate modification at operator discretion
• Primary outcome: freedom from AF recurrence at 12 months (after 3-month blanking period)
• AF recurrence defined as AF on 12-lead ECG, >30 seconds on Holter, or >5 minutes on CIED

Baseline Characteristics

• Gene-positive cohort: mean age 55.6 ± 9.9 years, 83% men; 66.6% had persistent AF (vs. 33.3% paroxysmal)
• Control cohort: mean age 61.5 ± 12.6 years, 60% men; 66.7% had paroxysmal AF
• Both cohorts had severely enlarged LAs (LAVI ~51.7 vs. 54.1 mL/m²), elevated LA pressures (~20 mmHg), and preserved EF
• MYBPC3 variant–positive patients had significantly greater LV mass index than MYH7 variant–positive (145.7 vs. 86.6 g/m²; P=0.04)
• Gene-positive cohort had higher rates of prior TIA/stroke (25% vs. 0%; P=0.04) — the only statistically significant baseline difference

Electroanatomical Mapping — LA Substrate

• Gene-positive cohort had significantly more LA abnormal voltage than controls:
  • Normal voltage (>0.5 mV): 87.7% vs. 94.3% (P<0.001)
  • Intermediate scar (0.1–0.5 mV): 6.33% vs. 3.07% (P<0.01)
  • Dense scar (<0.1 mV): 5.93% vs. 2.61% (P<0.01)
• Topological distribution of low-voltage areas was similar between gene-positive and control cohorts (no regional predilection as a group)
• MYH7 variant–positive patients had a greater predilection for dense scar in the lateral LA regions compared to MYBPC3 variant–positive
• No significant correlation between LA volume index, LA pressure, and degree of low-voltage areas — suggesting fibrosis is driven by genetic substrate, not hemodynamics

Ablation Strategy and Periprocedural Outcomes

• All patients underwent PVI; 11 patients underwent adenosine testing for dormant conduction
• Additional substrate modification in 6 gene-positive patients (posterior wall isolation n=2, roof line n=2, mitral isthmus line n=2) and 5 controls
• Cavotricuspid isthmus ablation in 9/12 gene-positive and 9/15 controls
• Periprocedural complications were rare: 1 patient developed postprocedural pericarditis (medically managed)
• All gene-positive patients were on AADs after index ablation

Primary Outcome: Freedom from AF at 12 Months

• Gene-positive: 75% free from AF at 12 months (9/12 patients)
• Controls: 73.3% free from AF at 12 months (11/15 patients)
• P=0.92 — no statistically significant difference
• No significant difference between MYBPC3 vs. MYH7 subgroups in primary outcome
• AF burden in CIED patients reduced from 57% (baseline) to 0.1% at 12 months in gene-positive patients achieving primary outcome

Late Recurrence and Repeat Ablation

• Late AF recurrence (≥12 months): 41.7% gene-positive vs. 26.7% controls (P=0.41)
• Mean number of procedures significantly higher in gene-positive cohort: 1.67 ± 0.65 vs. 1.20 ± 0.41 (P=0.03)
• Cumulative freedom from AF at last follow-up: 58.3% gene-positive vs. 60% controls
• In gene-positive redo procedures (7 patients): pulmonary vein reconnections in 5/7 (71%); interval progression of LA fibrosis in 5/7 (71%)
• Additional lesion sets at redo: SVC isolation (n=3), mitral isthmus lines (n=3), roof lines (n=2), posterior wall isolation (n=3)
• Atrial tachycardia (AT) noted in 25% gene-positive vs. 40% controls; mostly nonsustained post-ablation rhythms on CIED

Discussion

• Gene-positive HCM patients had appreciably more LA low-amplitude voltage areas than controls despite similar LA pressures — supporting primary atrial myopathy independent of hemodynamic effects
• This supports the hypothesis that MYBPC3/MYH7 variants promote AF through selective atrial myopathy, not just secondary pressure overload
• 5/7 gene-positive redo patients showed interval progression of fibrosis — suggesting ongoing atrial disease even after ablation
• Thicker LA walls (expected in MYBPC3 patients with greater LV mass) may result in non-transmural ablation lesions → more pulmonary vein reconnections
• ERASE-AF trial (not from this paper): PVI + low-voltage area ablation reduced AF recurrence at 12 months — raises possibility of substrate-guided ablation for these patients

Limitations of the Document

• Small sample size (n=27, 12 gene-positive): Statistically underpowered for subgroup analyses (MYBPC3 vs. MYH7); unable to detect modest differences in outcomes
• Single-center, retrospective design: Generalizability limited; non-standardized ablation lesion sets across operators
• Selection bias: Only patients with 3D electroanatomical maps available were included; a large proportion of eligible patients was excluded, limiting representativeness
• No standardized CIED monitoring: Not all patients had continuous monitoring; some AF recurrences may have been missed
• LA pressure measured at trans-septal puncture only: May not reflect typical resting LA pressure
• No quality-of-life or standardized symptom assessment
• Only MYBPC3 and MYH7 studied: Other HCM-causing genes not represented

Key Concepts Mentioned

• concepts/Atrial-Myopathy-in-HCM — central mechanism: genetic variants promote primary atrial fibrosis independent of LA pressure
• concepts/Catheter-Ablation-AF — PVI-based ablation strategy with additional substrate modification
• concepts/Late-Gadolinium-Enhancement — atrial fibrosis is the substrate for AF (electroanatomical surrogate)

Key Entities Mentioned

• entities/MYBPC3 — most common HCM gene; associated with greater LA fibrosis and more ablation procedures
• entities/MYH7 — second most common HCM gene; predilection for lateral LA dense scar
• entities/HCM — disease context; AF management within HCM
• entities/Atrial-Fibrillation — clinical condition being ablated

Wiki Pages Updated

• wiki/sources/MYBPC3-MYH7-JACCEP-2024.md — created (this page)
• wiki/entities/MYBPC3.md — added AF substrate and ablation outcome data
• wiki/entities/MYH7.md — added AF substrate and lateral scar predilection data
• wiki/entities/HCM.md — updated AF management section with genotype-specific ablation outcomes
• wiki/entities/Atrial-Fibrillation.md — added HCM-genotype atrial myopathy substrate
• wiki/concepts/Catheter-Ablation-AF.md — added HCM-genotype ablation section
• wiki/concepts/Atrial-Myopathy-in-HCM.md — created (new concept page)
• wiki/wikiindex.md — updated with new source entry