Comparison of temporal changes in left atrial and left ventricular strain after septal myectomy, alcohol septal ablation, and cardiac myosin inhibitor

This study demonstrates that while septal myectomy, alcohol septal ablation, and cardiac myosin inhibitors all effectively reduce LVOT gradients in obstructive hypertrophic cardiomyopathy, they exhibit distinct temporal patterns of myocardial functional adaptation, with surgical and ablative therapies showing progressive strain improvement whereas cardiac myosin inhibitors result in stable LV strain but late attenuation of left atrial strain.

The Gist

Imagine your heart is a busy, high-pressure highway. In a condition called obstructive hypertrophic cardiomyopathy (oHCM), the "road" leading out of the heart (the Left Ventricular Outflow Tract) gets blocked by a thick wall of muscle. This is like a traffic jam where the exit ramp is too narrow, causing cars (blood) to pile up, the engine to overwork, and the driver (the patient) to feel exhausted and short of breath.

For years, doctors had two main ways to fix this traffic jam:

1. Septal Myectomy (SM): A surgeon goes in and physically cuts away the extra muscle (like a construction crew removing a wall).
2. Alcohol Septal Ablation (ASA): A doctor injects alcohol into the specific artery feeding that muscle to kill it off, causing it to shrink (like using a controlled demolition to clear the blockage).

Recently, a new "traffic controller" arrived: Cardiac Myosin Inhibitors (CMI), a pill (mavacamten) that tells the heart muscle to relax and not squeeze as hard.

This study asked a simple question: Do these three methods fix the heart in the same way over time? The researchers looked at how the heart's "muscle fibers" stretched and squeezed (strain) over two years after treatment.

The Big Discovery: Clearing the Road vs. Changing the Engine

Here is the breakdown of what happened, using simple analogies:

1. The Traffic Jam (The Blockage)

Result: All three methods were great at clearing the traffic jam.
Whether they cut the wall, burned it, or told the muscle to relax, the pressure in the heart dropped significantly for almost everyone. The "exit ramp" was wide open in all three groups.

2. The Engine's Performance (The Left Ventricle)

This is where the methods started to differ. The researchers measured how well the heart muscle fibers stretched and squeezed (called Strain).

• The Surgery Groups (SM & ASA): Think of these patients as having a car that was previously stuck in mud. Once the mud (blockage) was removed, the car didn't just drive; it started to run better than before. Over time, the heart muscle fibers became more flexible and efficient. The "strain" improved gradually, like a runner who, after removing a heavy backpack, gets stronger and faster with every mile.
• The Pill Group (CMI): This group was like a car where the driver was told to "drive gently." The traffic jam was cleared, but the engine was also told to "take it easy." The heart's squeezing power (strain) stayed exactly the same—it didn't get better, but it didn't get worse either. However, there was a tiny catch: the overall engine power (Ejection Fraction) dipped slightly at the very beginning, like a car idling down when you first press the brake.

3. The Reservoir (The Left Atrium)

The left atrium is a small holding tank that catches blood before it goes into the main engine. When the main road is blocked, this tank gets overworked and stiff.

• The Surgery Groups: Once the blockage was gone, the tank relaxed, became more elastic, and started working efficiently again. It was like a deflated balloon being let go; it bounced back to its healthy shape.
• The Pill Group: The tank stayed the same for the first year, but then, surprisingly, it started to get a little stiff again after 9–12 months. It's as if the "gentle driving" instruction worked well for a while, but eventually, the tank didn't get the full benefit of the road being cleared.

The "So What?" for Patients

The study suggests that while the pill (CMI) is a fantastic, non-invasive option that works very well to clear the blockage, it acts differently than surgery.

• Surgery is like a permanent renovation. Once the wall is gone, the heart has the chance to remodel itself and become stronger and more efficient over the long haul.
• The Pill is like a temporary traffic manager. It works great while you are taking it, but it doesn't seem to give the heart the same "recovery boost" that surgery does. In fact, because it slows the heart down, we need to watch it closely to make sure the heart doesn't get too tired over many years.

The Bottom Line

If you have a blocked heart road:

• Surgery might give you a heart that not only clears the traffic but actually gets stronger and more flexible over time.
• The Pill clears the traffic effectively but keeps the heart's engine running at a "conservative" pace. It's a great option, especially for those who can't have surgery, but doctors need to keep a close eye on the heart's long-term flexibility, especially after the first year.

The study doesn't say one is "better" than the other; rather, it tells us they are different tools that change the heart in different ways. Knowing this helps doctors choose the right tool for the right patient, especially if they are young and need a solution that lasts a lifetime.

Technical Summary

1. Problem Statement

Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular outflow tract obstruction (LVOTO), leading to symptoms and adverse outcomes. The therapeutic landscape has shifted with the introduction of Cardiac Myosin Inhibitors (CMIs), such as mavacamten, which offer a pharmacologic alternative to invasive Septal Reduction Therapy (SRT) (specifically Septal Myectomy [SM] and Alcohol Septal Ablation [ASA]).

While all three modalities effectively reduce LVOT gradients, there is a lack of comparative data regarding their long-term temporal evolution on myocardial function. Specifically, it is unclear how these treatments differentially affect:

• Left Ventricular Global Longitudinal Strain (LVGLS): A sensitive marker of systolic function.
• Left Atrial Reservoir Strain (LASr): A marker of atrial function and compliance.
• Left Ventricular Ejection Fraction (LVEF): Conventional systolic function.

The study addresses the gap in understanding whether mechanical unloading (SRT) or pharmacologic sarcomere inhibition (CMI) leads to distinct patterns of myocardial and atrial adaptation over time.

2. Methodology

• Study Design: Single-center, retrospective observational cohort study conducted at Seoul National University Bundang Hospital.
• Population: Symptomatic oHCM patients (NYHA class II–IV) with significant LVOTO despite medical therapy.
  • Cohorts: Septal Myectomy (SM, n=22), Alcohol Septal Ablation (ASA, n=11), and Cardiac Myosin Inhibitor (CMI, n=47).
  • Inclusion Criteria: Clinically significant LVOTO; successful treatment defined as post-treatment LVOT gradient <50 mmHg within 6 months.
• Data Collection: Serial echocardiography performed over a 24-month follow-up period.
• Advanced Imaging Analysis:
  • Used a deep-learning-based automated strain analysis platform (Sonix Health Workstation) to quantify LVGLS and LASr.
  • This approach minimized inter-observer variability and was validated for use in HCM patients undergoing SRT or CMI.
• Statistical Analysis:
  • Generalized Additive Mixed Models (GAMMs) with restricted cubic splines were used to model non-linear time trajectories.
  • Models were adjusted for baseline demographics (age, sex), comorbidities, and baseline echocardiographic parameters (LVOT gradient, LVEF, LVMI, E/e').
  • Primary outcomes: Temporal trajectories of LVGLS and LASr.

3. Key Contributions

• First Direct Comparison: This is the first study to directly compare the longitudinal deformation trajectories (LVGLS and LASr) across all three contemporary treatment strategies (SM, ASA, CMI) over a 2-year period.
• Differentiation of Mechanisms: It distinguishes between the functional recovery patterns of mechanical unloading (SRT) versus pharmacologic contractility reduction (CMI).
• Validation of Deep Learning: Demonstrates the utility of automated, deep-learning-based strain analysis in tracking subtle, time-dependent changes in HCM patients across different treatment modalities.
• Long-Term Safety Signal: Provides early evidence regarding the "late attenuation" of atrial function in patients on long-term CMI therapy, a parameter not previously well-characterized in this context.

4. Key Results

Baseline Characteristics:

• The SM group was younger with higher LV mass index (LVMI) and LVOT gradients.
• The ASA group was the oldest with the highest comorbidity burden.
• The CMI group had the lowest LVMI and LVOT gradients but the highest proportion of NYHA Class II symptoms.

Treatment Success:

• CMI had the highest success rate (93.6%), followed by SM (86.4%) and ASA (72.7%).
• All groups achieved comparable reductions in LVOT gradients post-treatment.

Temporal Changes in LV Function:

• LVEF: Showed a subtle early decline in the CMI group compared to SRT groups (Adjusted P-for-interaction = 0.019).
• LVGLS:
  • SM & ASA: Demonstrated progressive improvement over 24 months.
  • CMI: Remained stable (unchanged) throughout the follow-up period.
  • Interpretation: Mechanical unloading allows for functional recovery of global longitudinal strain, whereas sarcomere inhibition maintains a stable but non-improving strain profile.

Temporal Changes in LA Function:

• LASr (Left Atrial Reservoir Strain):
  • SM: Showed significant progressive improvement over time.
  • ASA: Showed minimal change.
  • CMI: Remained stable for the first 9 months but demonstrated late attenuation (decline) beyond 9–12 months (Adjusted P = 0.029).
• LAVI (Left Atrial Volume Index): Decreased in SM and ASA groups but showed a mild increase in the CMI group (though not statistically significant after adjustment).

Adverse Events:

• SM was associated with procedural risks (pacemaker implantation in 13.6%, new VSD in 4.5%).
• No new-onset arrhythmias or procedural complications were observed in the ASA or CMI groups.

5. Significance and Clinical Implications

• Reappraisal of SRT: Despite the rise of CMIs, conventional SRT (SM/ASA) appears to offer superior myocardial functional recovery (improvement in LVGLS and LASr) compared to the stable but non-improving profile of CMI. This suggests that mechanical relief of obstruction facilitates reverse remodeling that pharmacologic inhibition does not fully replicate.
• Monitoring CMI Therapy: The study highlights the need for serial deformation imaging (specifically LASr) in patients on CMI. The observed late attenuation of atrial strain suggests potential long-term risks of atrial dysfunction or arrhythmia that may not be captured by LVEF alone.
• Treatment Selection:
  • CMI may be preferred for patients with high procedural risk or those requiring a non-invasive first-line approach, given its high hemodynamic success rate.
  • SRT may be favored for younger patients or those requiring durable, long-term functional improvement, provided the procedural risk is acceptable.
• Future Directions: The findings underscore the need for longer-term studies to determine if the late attenuation of LASr in CMI patients translates to clinical adverse events (e.g., atrial fibrillation) and to refine patient selection criteria between mechanical and pharmacologic therapies.

Conclusion: While all three therapies effectively reduce LVOT gradients, they induce distinct myocardial and atrial remodeling patterns. SRT is associated with progressive functional improvement, whereas CMI is associated with stable LV strain but late attenuation of atrial strain, necessitating careful long-term monitoring.