Anatomy of the Isthmus: Unraveling the Tissue Composition of the Ventricular Tachycardia Diastolic Pathway.

BACKGROUND

A protected, slow-conducting diastolic pathway (isthmus) is the electrophysiological hallmark of post-myocardial infarction (MI) re-entrant ventricular tachycardia (VT). Contemporary evaluations of the histologic composition promoting slow, protected conduction during VT are lacking.

OBJECTIVES

The goal of this study was to compare the histologic characteristics of confirmed VT isthmuses (VTIs) and non-isthmus scar (NIS) in a chronic MI swine model.

METHODS

One month after non-reperfused anterior MI, nine Landrace X Large White pigs with inducible VT underwent high-density activation mapping to define the diastolic corridor. Radiofrequency lesions were created to guide the ex vivo VTI localization. Tissue transverse samples from the labeled VTI and NIS were obtained for further histologic, immunohistochemical, and RNA-sequencing expression analyses.

RESULTS

Compared with NIS, VTI showed significantly higher fatty infiltration (P = 0.012) and lower levels of collagen I (P = 0.053), collagen III (P = 0.043), and collagen volume fraction (P = 0.027); there were no differences in overall fibrotic deposition. VTI exhibited greater vascular density compared with NIS (P = 0.018), with arteries and veins primarily surrounded by preserved cardiomyocytes. Compared with NIS, viable cardiomyocytes and fibroblasts in VTI displayed higher densities of connexin 43 and connexin 40 (P = 0.022 and P = 0.004, respectively), despite no differences in cardiac troponin I, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2, or vimentin expression. Thirty-six genes, involving pathways related to extracellular matrix remodeling, inflammation, and immune response modulation, were differentially expressed between VTI and NIS.

CONCLUSIONS

The VTI exhibits a distinct histologic composition and differential gene expression compared with the surrounding NIS. Mid-diastolic activation sites showed increased adipocytic deposition, vascularization, and connexin expression, along with lower levels of collagen I, collagen III, and collagen volume fraction.