Electrophysiological effects of adipose graft transposition procedure (AGTP) on the post-myocardial infarction scar: A multimodal characterization of arrhythmogenic substrate

Abstract

Objective: To assess the arrhythmic safety profile of the adipose graft transposition procedure (AGTP) and its electrophysiological effects on post-myocardial infarction (MI) scar.

Background: Myocardial repair is a promising treatment for patients with MI. The AGTP is a cardiac reparative therapy that reduces infarct size and improves cardiac function. The impact of AGTP on arrhythmogenesis has not been addressed.

Methods: MI was induced in 20 swine. Contrast-enhanced magnetic resonance (ce-MRI), electrophysiological study (EPS), and left-ventricular endocardial high-density mapping were performed 15 days post-MI. Animals were randomized 1:1 to AGTP or sham-surgery group and monitored with ECG-Holter. Repeat EPS, endocardial mapping, and ce-MRI were performed 30 days post-intervention. Myocardial SERCA2, Connexin-43 (Cx43), Ryanodine receptor-2 (RyR2), and cardiac troponin-I (cTnI) gene and protein expression were evaluated.

Results: The AGTP group showed a significant reduction of the total infarct scar, border zone and dense scar mass by ce-MRI (p = 0.04), and a decreased total scar and border zone area in bipolar voltage mapping (p < 0.001). AGTP treatment significantly reduced the area of very-slow conduction velocity (<0.2 m/s) (p = 0.002), the number of deceleration zones (p = 0.029), and the area of fractionated electrograms (p = 0.005). No differences were detected in number of induced or spontaneous ventricular arrhythmias at EPS and Holter-monitoring. SERCA2, Cx43, and RyR2 gene expression were decreased in the infarct core of AGTP-treated animals (p = 0.021, p = 0.018, p = 0.051, respectively).

Conclusion: AGTP is a safe reparative therapy in terms of arrhythmic risk and provides additional protective effect against adverse electrophysiological remodeling in ischemic heart disease.

Keywords: adipose graft transposition procedure; arrhythmic risk; mapping; myocardial infarction; myocardial repair; ventricular tachycardia.

FIGURE 1

Chronogram and workflow of the study. ce-MRI, contrast-enhanced magnetic resonance imaging; HD, high density; LV, left ventricular; EPS, electrophysiological study.

FIGURE 2

Contrast-enhanced MRI-based tissue characterization. Representative examples of post-MI substrate remodeling at 30-day follow-up. Favorable remodeling was observed in the AGTP group (upper panel), with a significant reduction in border zone (BZ) and dense scar and a trend toward reduced BZ corridors. Sham group (lower panel) showed increased scar volume and a trend toward development of new BZ corridors.

FIGURE 3

Baseline and follow-up mapping data. Boxplots shows significant differences in the area of border zone tissue (A), number of deceleration zones (B), very-slow conduction velocity (C), and highly fractionated electrogram area (D). BZ, border zone; CV, conduction velocity; DZ, deceleration zones.

FIGURE 4

Scar detection by endocardial mapping. High density endocardial mapping of the left ventricle showing post-MI low voltage area. After 30 days, animals receiving AGTP showed a reduction in border zone area (0.5–1 mV) (upper panel) whereas those in the Sham group showed overall increase in total scar area (bottom panel).

FIGURE 5

Isochronal mapping and deceleration zones. Representative isochronal activation maps of AGTP (top) and sham-surgery (bottom) animals; the AGTP group showed significant reduction in the number of deceleration zones over time, whereas an increase was observed in the sham subjects (A). (B) Illustrates an example of a follow-up high density map of a sham subject exhibiting a late and fractionated electrogram (yellow box) at the latest activation area (infero-basal left ventricular wall).

FIGURE 6

Gene and protein expression profiles. (A) cTnI, Cx43, SERCA2, and RyR2 gene expression in sham (n = 7) and AGTP-treated (n = 6) animals determined by normalizing the expression for each gene to GUSB following the 2^{–Δ Ct} method. (B) Western Blot images of RyR2 presence and the respective Ponceau S staining to depict protein loading (top) and the corresponding histogram of RyR2 protein expression of sham and AGTP groups (bottom). (C) cTnI, Cx43, and RyR2 protein expression determined by western blot in sham and AGTP-treated animals represented in boxplots.

Central Illustration

Experimental model and main findings of the study. BZ, border zone; DZ, deceleration zones; EGM, electrogram; EPS, electrophysiological study; HD, high density; MRI, magnetic resonance imaging.