Programmed Ventricular Stimulation Induction Threshold Does Not Predict Arrhythmic Burden in Ischemic and Non-Ischemic Cardiomyopathy: A Single- Center Prospective Registry

Technical Summary: Programmed Ventricular Stimulation Induction Threshold in Cardiomyopathy

Problem Statement
Sudden cardiac death (SCD) remains a primary cause of cardiovascular mortality, particularly in patients with structural heart disease and reduced left ventricular ejection fraction (LVEF). While LVEF ≤35% is the established threshold for primary prevention implantable cardioverter-defibrillator (ICD) implantation, a significant "gray zone" exists for patients with mildly reduced LVEF (36–50%), unexplained syncope, or non-ischemic cardiomyopathy (NICM) where LVEF is a less reliable predictor. In these populations, Programmed Ventricular Stimulation (PVS) is utilized to probe the myocardial substrate for inducible ventricular tachycardia (VT). However, a critical knowledge gap remains regarding the prognostic value of the induction threshold. Clinicians often operate under the intuition that patients requiring fewer extrastimuli (e.g., a single extrastimulus, S2) to induce VT harbor a more dangerous substrate than those requiring aggressive protocols (e.g., triple extrastimuli, S4+). This hypothesis, validated in channelopathies like Brugada syndrome, has not been rigorously tested in structural cardiomyopathies where VT is driven by fixed anatomical re-entry.

Methodology
The authors conducted a prospective, single-center observational registry at Sismanogleio General Hospital in Athens, Greece, enrolling 66 consecutive heart failure patients referred for PVS between January 2024 and May 2025. The cohort included patients with Ischemic Cardiomyopathy (ICM, n=36) and Non-Ischemic Cardiomyopathy (NICM, n=30) who fell into the clinical gray zone for primary prevention ICD.

• Stimulation Protocol: PVS was performed using a hierarchical approach from the right ventricular apex. The protocol progressed from a single extrastimulus (S2) to double (S3) and triple (S4) extrastimuli, followed by burst pacing if necessary. Antiarrhythmic drugs were withheld prior to the procedure.
• Classification: A positive test was defined as the induction of sustained monomorphic VT (≥30 seconds or hemodynamic compromise). Patients with positive tests were categorized by their induction threshold: Low (S2), Moderate (S3), or High (S4+).
• Follow-up: All patients with positive PVS underwent ICD or CRT-D implantation. The primary endpoint was the occurrence of any ventricular arrhythmic episode (sustained VT requiring therapy or non-sustained VT/ATP) detected during device interrogation at 12 months.
• Statistical Analysis: Event rates were compared across threshold categories using chi-square tests and the Cochran–Armitage trend test to evaluate for linear trends.

Key Results

• Inducibility: PVS successfully induced sustained monomorphic VT in 54 of 66 patients (81.8%). Inducibility was significantly higher in ICM (94.4%) compared to NICM (66.7%).
• Threshold Distribution: Among the 54 positive patients, the induction thresholds were: S2 (n=4, 7.4%), S3 (n=16, 29.6%), and S4+ (n=34, 63.0%). Notably, no NICM patient was induced at the S2 level; all NICM inductions required S3 or S4+ protocols.
• Arrhythmic Burden: Over 12 months, 9 of the 54 positive patients (16.7%) experienced arrhythmic events. The distribution of events was:
  • S2 Group: 0 events (0/4).
  • S3 Group: 1 event (6.2%, 1/16).
  • S4+ Group: 8 events (23.5%, 8/34).
• Statistical Significance: Despite the numerical trend of increasing event rates with more aggressive induction protocols (S2 < S3 < S4+), the association was not statistically significant (Chi-square p=0.20; Cochran–Armitage trend p=0.084).
• Etiology Differences: NICM patients exhibited a higher overall event rate (25.0%) compared to ICM patients (11.8%). Within the ICM subgroup, all 4 events occurred in the S4+ group.
• Demographics: Age and LVEF did not significantly differentiate patients who experienced events from those who did not.

Key Contributions and Claims
The study challenges the prevailing clinical intuition that the "ease" of VT induction correlates inversely with arrhythmic risk in structural heart disease. The authors claim that:

1. Binary Inducibility is the Primary Marker: The presence of inducible monomorphic VT is a robust predictor of arrhythmic risk (16.7% event rate at 12 months), regardless of the stimulation protocol required to elicit it.
2. Threshold Does Not Predict Outcome: The specific induction threshold (S2 vs. S3 vs. S4+) did not predict the burden of arrhythmic events. Contrary to the hypothesis, patients requiring the most aggressive protocols (S4+) had numerically higher event rates than those induced with single extrastimuli.
3. Mechanistic Distinction: The authors posit that unlike channelopathies (e.g., Brugada syndrome) where induction ease reflects substrate instability, structural cardiomyopathy VT is driven by anatomical re-entry. A patient with a discrete, easily inducible circuit may not have frequent spontaneous events, whereas a patient with a diffuse, heterogeneous substrate (requiring S4+) may be prone to spontaneous arrhythmia despite being harder to induce in the lab.
4. Clinical Implications for NICM: The findings support the utility of PVS in NICM patients, a group where LVEF-based criteria have shown limited mortality benefit (referencing the DANISH trial). A positive PVS result in NICM was associated with a 25% event rate, suggesting a clear indication for ICD therapy in this subgroup.

Significance and Limitations
The paper concludes that PVS positivity itself, rather than the induction threshold, serves as the actionable prognostic signal for ICD implantation in gray-zone cardiomyopathy patients. The authors argue against de-escalating clinical decisions based on the number of extrastimuli required for induction.

The study acknowledges modesty in its claims due to several limitations:

• Sample Size: The study was underpowered, particularly for the S2 group (n=4), which resulted in wide confidence intervals and a lack of statistical significance for the observed trends.
• Single-Center Design: Generalizability may be limited.
• Follow-up Duration: A 12-month follow-up may be insufficient to capture the full arrhythmic trajectory.
• Exclusion of Negative PVS: The study did not follow patients with negative PVS, preventing sensitivity/specificity calculations.

The authors assert that larger, multicenter studies with extended follow-up are necessary to confirm these observations and refine the role of PVS in arrhythmic risk assessment.