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 the electromechanical coupling for maximal contractile efficiency of the heart. 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."

Keywords: Cardiac arrhythmia; Dispersion of refractoriness; Fibrosis; Myofibroblast; Reentry; Source–sink mismatch.

Fig. 1

Cardiac fibrosis patterns. Red = collagen; yellow = myocardium. The most arrhythmogenic patterns are interstitial and patchy, which result in interconnected strands of myocytes separated by collagen bundles. Modified from de Jong et al [14] with permission.

Fig. 2

Slow conduction in the border zone of an infarct manifests as fractionated electrograms. Intracellular microelectrode recordings show action potentials from sites A–D in strands of myocytes (solid gray) surrounded by collagen bundles (speckled gray). A simultaneously recorded bipolar electrogram (white circles) is shown below each local action potential recording. Note that the timing of the action potential upstroke at sites A–D each coincides with a spike in the electrogram. Reproduced from Gardner et al [15] with permission.

Fig. 3

Classic mechanism by which a PVC initiates reentry in the fibrotic border zone of an infarct due to slow conduction and dispersion of refractoriness. Upper panel: A PVC occurring 250 ms after the previous beat arrives too early to propagate through the upper myocyte strand with a long effective refractory period (ERP) of 275 ms but propagates successfully (red arrows) through the lower strand with a shorter ERP of 225 ms (entry site). The impulse propagates slowly (slow CV), eventually reaching the upper strand from the opposite direction. Lower panel: If the total conduction time is >275 ms, the interface of the upper strand with normal tissue (exit) site has recovered excitability and the impulse can propagate through the region of prior conduction block, initiating reentry. Dispersion of refractoriness is caused by electrical remodeling. The slow propagation is due to zig-zag conduction through the myocyte strands as well as gap junction remodeling.

Fig. 4

Source-sink effects and the initiation of reentry in the border zone of an infarct. Upper panel: A PVC originating from within the lower myocyte strand propagates in both directions (red arrows) but blocks at the interface with normal tissue due to the unfavorable source-sink mismatch (i.e. the small source of the strand faces a large sink at the interface with well-coupled 3D tissue). Meanwhile, the impulse propagates slowly in the other direction (through the scar), eventually reaching the upper strand which widens progressively before the interface with normal tissue. The gradual widening ensures that current density in the strand progressively increases (thickening arrows), creating a more favorable source-sink relationship at the interface, ensuring successfully propagation into the normal tissue. Lower panel: Due to the slow conduction, the lower strand has recovered excitability, allowing the impulse from normal tissue to enter the strand and propagate since the source-sink relationship in the opposite direction is highly favorable. Reentry is thus initiated without requiring any dispersion of refractoriness between the myocyte strands and/or the normal tissue. Note that a PVC arising from the normal tissue (e.g. as during programmed electrical stimulation) will encounter favorable source-sink relationships at the entrance to both strands such that the propagating impulses will collide in the strand and extinguish each other, failing to initiate reentry. Note also that during reentry, the entry site is narrow, whereas the exit site is broad, making the entry site, if identifiable, the more favorable for catheter ablation.

Fig. 5

The effect of myofibroblast-myocyte coupling on EAD and DAD formation. A paced rabbit ventricular myocyte exposed to hypokalemia exhibited a normal action potential (upper trace) with very small DADs until coupled to a virtual fibroblast (capacitance 6.3 pF, gap junction conductance 3.0 nS, uncoupled resting membrane potential E_f −50 mV), which caused EADs to appear and DADs (arrows) to grow larger in amplitude (middle trace). Effects were more even more prominent when the virtual fibroblast resting membrane potential E_f was lowered to −25 mV (bottom trace), which resulted in a DAD-triggered premature action potential (arrow) before the pacing spike. Reprinted from Nguyen et al [3] with permission.

Fig. 6

Summary of the role of fibroblasts in cardiac arrhythmogenesis.