Electrophysiological Consequences of Cardiac Fibrosis

Abstract

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.

A Review of Healthy and Fibrotic Myocardium Microstructure Modeling and Corresponding Intracardiac Electrograms

“…The zig-zag pattern of the propagation is reflected in uEGM and biEGM as fractionation in the signal due to constantly changing orientation of the wavefront. Fractionation is defined as an increase of deflections, thus an increase in complexity of the signal as well as a prolongation of the EGM ( Jacquemet and Henriquez, 2009 ; Verheule and Schotten, 2021 ). As previously mentioned, the highpass filter cut-off value affects the signal amplitude.…”

Cardiac Macrophages and Their Effects on Arrhythmogenesis

“…Aside from altered impulse formation, abnormal impulse conduction represents another main mechanism of arrhythmogenesis ( Nguyen et al, 2017 ). This can be caused by anatomic changes (such as hypertrophy or fibrosis) indirectly influencing conduction, by altered electrical conduction properties itself (functional reentry, e.g., by modified gap junction expression/function) ( Kamjoo et al, 1997 ) as well as by changes in autonomic tone ( Verheule and Schotten, 2021 ).…”

“…Such a delayed impulse conduction, which also happens after myocardial infarction where a myocardial scar acts as a central obstacle, allows the myocardium to recover from a previous excitation. The following depolarizing front can continuously encounter excitable myocardium, thereby promoting circular excitation, so-called reentry ( Verheule and Schotten, 2021 ). A murine TGF-β1 overexpression model for example shows that atrial fibrosis itself is sufficient to cause AF ( Verheule et al, 2004 ).…”

Recent Non-Invasive Parameters to Identify Subjects at High Risk of Sudden Cardiac Death

“…Increased left ventricular (LV) mass is associated with an increased risk of SCD in the general population [ 48 , 49 ]. LVH is associated with abnormal interstitial remodeling which can impair electrical conduction and promote Vas [ 50 ]. In the Framingham Heart Study, increased LV mass and hypertrophy as assessed by echocardiogram, were independently associated with SCD after accounting for other known risk factors [ 51 ].…”