Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?

American Journal of Cardiovascular Disease

Hrayr S Karagueuzian¹ 

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

DOI  :  

学科分类：心脏病和心血管学

来源: e-Century Publishing Corporation

【 摘 要 】

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 (H2O2) 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.

【 授权许可】

CC BY-NC