Arrhythmogenic cardiomyopathy is characterized by apex-to-base heterogeneity of right ventricular myocardial contractility and stiffness: an imaging-based patient-specific modeling study
Authors: Van Osta N , Lyon A , Kirkels F , Koopsen T , Van Loon T.A.M , Cramer M.J , Teske A.J , Delhaas T , Lumens J 
Published: November 2020

Abstract

Introduction
Arrhythmogenic Cardiomyopathy (AC) is an inherited cardiac disease, clinically characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Geno-positive subjects with and without symptoms may suffer from sudden cardiac death. Therefore, early disease expression and risk stratification is important. It has been shown that right ventricular (RV) longitudinal deformation abnormalities in early stages is related to disease progression. We propose an inverse patient-specific computer modelling approach, combined with clinical imaging data, to non-invasively quantify regional ventricular tissue abnormalities in AC mutation carriers.

Purpose
To non-invasively reveal the individual myocardial substrate underlying the regional RV deformation abnormalities in AC mutation carriers.

Methods
In 74 individuals carrying a plakophilin-2 or desmoglein-2 mutation, regional longitudinal deformation patterns of the RV free wall (RVfw), interventricular septum (IVS) and left ventricular free wall (LVfw) were obtained using speckle-tracking echocardiography (Figure: left column). This cohort was subdivided into 3 consecutive clinical stages i.e. subclinical (concealed, n=19) with no abnormalities, electrical stage (n=13) with only electrocardiographic abnormalities, and structural stage (n=42) with both electrical and structural abnormalities defined by the 2010 Task Force AC criteria. We developed and used a patient-specific parameter estimation protocol based on the multi-scale CircAdapt cardiovascular system model to create virtual AC subjects (Figure: middle column). Using the individuals' RV strain patterns as model input, this protocol automatically estimated regional RV tissue properties, such as myocardial contractility and stiffness.

Results
The computational model was able to reproduce the deformation as clinically measured. Patient-specific parameter estimation results (Figure: right column) revealed that clinical AC disease progression is characterized by an increase of base-to-apex heterogeneity in contractility and stiffness of the RV myocardial tissue, with a decreased contractility and an increased stiffness in the basal segment compared to the apex. Although this heterogeneity was most severe in the structural stage group, it was already present in many of the subjects in the subclinical stage. No clear apex-to-base heterogeneity of mechanical activation delay was found in this cohort.

Conclusion
Our patient-specific modelling approach showed that early abnormalities in RV longitudinal strain are most likely caused by increased heterogeneity in local tissue properties. Strain abnormalities are predominantly caused by decreased basal tissue contractility and increased basal tissue stiffness. Abnormalities in tissue properties may be found already in the subclinical stage. Future studies will investigate how these abnormalities relate to disease progression and arrhythmogenic risk.
Characterization of AC Disease Substrate

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Netherlands Organisation for Scientific Research and the Dutch Heart Foundation.