Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?

Abstract

Cardiac fibrosis is known to alter cardiac conduction and promote reentry. Recent evidence indicates that fibrosis characterized by increased interstitial collagen accumulation and increased myofibroblast proliferation also promotes enhanced automaticity and early afterdepolarizations (EADs) causing triggered activity. Fibrosis then becomes an effective therapeutic target for the management of lethal cardiac arrhythmias. While oxidative stress with hydrogen peroxide (H(2)O(2)) is shown to readily promote EADs and triggered activity in isolated rat and rabbit ventricular myocytes however, this same stress fails to cause EADs in well-coupled, non-fibrotic hearts due to source-to-sink mismatches arising from cell-to-cell coupling. The triggered activity in the aged fibrotic hearts causes focal ventricular tachycardia (VT) that degenerates within seconds to ventricular fibrillation (VF) after the emergence of spatially discordant action potential duration alternans leading to wavebreak, reentry and VF. Computer simulations in 2D tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or very severe) fibrosis promoted EADs and TA. Human studies have shown that myocardial fibrosis was an independent predictor for arrhythmias including sustained VT and VF. A variety of drug classes including, torsemide, a loop diuretic, that inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules and the inhibitors of the renin-angiotensin-aldosterone system (RAAS), the mineralocorticoid receptors and endothelin receptors reduce cardiac fibrosis with reduction of myocardial stiffness and improved ventricular function. It is hoped that in the near future effective antifibrotic drug regimen would be developed to reduce the risk of fibrosis related VT and VF.

Keywords: Early afterdepolarization; discordant alternans; fibrosis; myofibroblast; optical mapping; oxidative stress; triggered activity; ventricular fibrillation; ventricular tachycardia.

Figure 1

Spontaneous initiation of VT/VF in an aged rat heart exposed to 0.1 mM H₂O₂. Panel A is an ECG showing the last 5 sinus beats before the sudden onset of VT leading to VF. Panel B are voltage snap shots of the last beat of the VT (beats #1) and of the first two beats of the VF (beats #2 & #3). In each snap shot activation time in ms is shown at the bottom right with time zero (arbitrary) coinciding with the onset of beat #1. The red color in the snap shots represents depolarization and the blue repolarization as shown in panel E. The yellow arrows in the snap shots represent the direction of the wavefront propagation with double horizontal lines denoting the site of conduction block. The VT originates from a focal site at the LV base and propagates as single wavefront towards the apex and undergoes functional conduction block at site 3. The two lateral edges of the front however, continue to propagate laterally (snap shot 98 ms) forming f igure-8 reentry (snap shot 108). During the second reentrant wavefront another wavefront emerges from the apical site of the LV (snap shot 122 ms) disrupting the activation pattern and signaling the onset of VF. Panel D, shows 3 optical action potentials (labeled 1, 2 and 3) recorded from sites identified on the heart silhouette (panel C). The two downward pointing blue arrows indicate the direction of propagation from site 1 to site 3 with the red downward pointing arrow showing block at site 3 followed by retrograde activation (upward pointing arrow). Notice the emergence of spatially discordant action potential duration (APD) alternans preceding conduction block at site 3 when the front with short APD (S) at site 1 encroaches a site (site 3) with long APD (L). S indicates short and L long APD. (From reference number 10, Morita et al)

Figure 2

Simultaneous microelectrode and ECG recordings at the onset of VT/VF in an aged rat heart exposed to 0.1 mM H₂O₂. Panel A, onset of early afterdepolarization (EAD)-mediated triggered activity (TA) causing ventricular tachycardia (VT) 5 min after H₂O₂ exposure. Note the smooth emergence of EAD (upward pointing arrow) during the isoelec-tric interval on the ECG followed by a run of 10 TA (downward pointing arrow) causing non-sustained VT on the ECG. The onset of the EAD precedes the QRS complex of the VT by 8 ms indicating absence of electrical activity elsewhere in the heart. Two additional short runs of VT with 4 beats each are also shown that follow a single subthreshold EAD (downward small arrow) with no TA. Panel B shows the degeneration of the TA to VF 15 min after H₂O₂ exposure. (From reference number 10, Morita et al)