Cardiac fibrosis and arrhythmogenesis: The road to repair is paved with perils

Abstract

In the healthy heart, cardiac myocytes form an electrical syncytium, embedded in a supportive fibroblast-rich extracellular matrix designed to optimize electromechanical coupling for maximal contractile efficiency of the heart pump. In the injured heart, however, fibroblasts are activated and differentiate into myofibroblasts that proliferate and generate fibrosis as a component of the wound-healing response. This review discusses how fibroblasts and fibrosis, while essential for maintaining the structural integrity of the heart wall after injury, have undesirable electrophysiological effects by disrupting the normal electrical connectivity of cardiac tissue to increase the vulnerability to arrhythmias. We emphasize the dual contribution of fibrosis in altering source-sink relationships to create a vulnerable substrate while simultaneously facilitating the emergence of triggers such as afterdepolarization-induced premature ventricular complexes– both factors combining synergistically to promote initiation of reentry. We also discuss the potential role of fibroblasts and myofibroblasts in directly altering myocyte electrophysiology in a pro-arrhythmic fashion. Insight into these processes may open up novel therapeutic strategies for preventing and treating arrhythmias in the setting of heart disease as well as avoiding potential arrhythmogenic consequences of cell-based cardiac regeneration therapy. This article is part of a Special Issue entitled “Myocyte-Fibroblast Signaling in Myocardium.”

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

“…Indeed, Ly‐6C low macrophage has been shown to play a crucial role in the pathogenesis and progression of the healing myocardium 30. In addition, macrophage‐induced fibrosis and several cytokines could aggravate arrhythmogenic properties 32, 33. We found that levels of fibrosis and inflammation were significantly elevated after myocardial infarction.…”

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…Importantly, fibrosis contributes to increased stiffness, impairing relaxation and filling of the LV during diastole and closely associates with diastolic dysfunction in HFpEF. 82 Moreover, fibrosis increases the risk of arrhythmias, 83 and fibrotic remodeling may cause cardiomyocyte slippage, thus affecting systolic function. 84 Cardiac fibrosis results from changes in the cellular and extracellular environment and is mainly regulated by activated fibroblasts (discussed below).…”

Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue

“…7 B). This may be a factor explaining the increased susceptibility of fibrotic tissue to DAD-mediated TA, because fibrosis creates myocyte strands acting functionally as quasi-1D cables embedded in 2D or 3D tissue (29). Similarly, other factors being equal, the Ca-voltage coupling gain required for a DAD to trigger an AP would be lower in Purkinje fibers (also quasi-1D cables) than in 3D myocardium.…”