Atrial fibrosis is one of the fundamental mechanisms
Atrial fibrosis is one of the fundamental mechanisms for the pathogenesis of atrial fibrillation (AF), but the underlying electrophysiological changes involved are not completely understood. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate various signaling pathways that lead to cellular hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix (ECM), such as tissue fibrosis; these may lead to disruption of the electrical side-to-side junctions between muscle bundles , resulting in electrical dissociation. Cardiomyocytes and cardiac fibroblasts are 2 major myocardial cell types, which constitute <50% and 40–60% of the total cell population, respectively . In normal adult hearts, quiescent fibroblasts substantially outnumber myocytes, and in response to hemodynamic stress or injury, these fibroblasts differentiate into myofibroblasts that proliferate, secrete collagen, and synthesize new proteins such as α-smooth muscle focal adhesion kinase (α-SMA), stretch-sensitive ion channels, and connexins . Fibroblasts have arrhythmogenic properties such as those involved in blocking impulse propagation and differentiation into myofibroblasts, which have contractility, have electrical connectivity and stimulate electrical impulse. The alteration of fibroblast-induced electrical impulses depends on the number of fibroblasts: small numbers of fibroblasts lead to slow impulse conduction whereas large numbers of fibroblasts lead to conduction block . Recently, the mechanism of cardiac fibrosis moved from fibroblast-induced electrical impulse propagation alteration to myofibroblasts, which is a key factor of the proarrhythmic mechanism. During embryonic development, mesenchymal cells migrate from the proepicardium to the epicardium, where they differentiate into epicardial-derived cells, which differentiate into fibroblast or myofibroblast phenotypes. Although phenotypically most of these epicardial-derived cells differentiate into fibroblasts, these cells can differentiate into myofibroblasts in response to injury or stress . The incidence of fibrosis increases after fibroblasts are transformed to activated fibroblasts or myofibroblasts . Myofibroblasts have contractile proteins and α-smooth muscle actin (SMA), which is a smooth muscle cell marker with enhanced migratory and proliferative properties . Transforming growth factor-β (TGF-β) has shown to induce differentiation of fibroblasts to myofibroblasts in cultures . Fibroblasts also differentiated to myofibroblasts in connexin-abundant cultures, especially in cultures mimicking the post-myocardial infarction (MI) state . Askar et al. reported that cardiomyocyte hypertrophy and fibrosis induced by myofibroblast proliferation have similar arrhythmogenicity. This study reported that prolonged action potential durations (APDs) and early after depolarization (EAD)-triggered activity observed in cultured hypertrophic and fibrotic tissue led to a high incidence of spontaneous re-entrant arrhythmias or focal arrhythmias . In addition, they found that high myofibroblast contents in cardiac cultures were associated with depolarized membrane potentials in cardiomyocytes, prolonged APD, and increased incidence of EADs that lead to arrhythmias . Arrhythmogenicity may also be induced by paracrine factors secreted by fibroblasts. The paracrine effect of post-MI-activated fibroblasts prolongs APD and slows conduction velocity . Adult murine cardiomyocytes developed significant cellular hypertrophy when treated with fibroblast-conditioned media, and when co-cultured with cardiac fibroblasts, they secreted high levels of atrial natriuretic peptide . Interestingly, conduction velocity increased and APD reduced in these cultures with MI heart myofibroblasts compared with cultures with normal heart fibroblasts . Here, mathematical models could be used for evaluating the myocyte–fibroblast electrical interaction. Fibroblasts can influence conduction velocity by obstructing, creating electrotonic load, and depolarizing myocytes. Since myofibroblasts have a less negative resting membrane potential, they can depolarize myocytes sufficiently to induce spontaneous pacemaking when the myofibroblast population exceeds 15% in co-cultures . Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Such a myofibroblast–myocyte coupling can trigger an arrhythmia such as EAD, and these mechanisms may contribute to the proarrhythmic risk in fibrotic hearts via spontaneous impulse formation and rotor-driven re-entry . The increase in the resting membrane potential of cardiomyocytes to more depolarized fibroblasts by coupling can result in an increase of conduction velocity even at low fibroblast concentrations . Similar to a low fibroblast number, even weak electrical coupling (gap junction connectivity) between myocytes and fibroblasts can slightly increase the resting membrane potential and conduction velocity of cardiomyocytes. At intermediate coupling levels, fibroblasts act as a current capacitor, resulting in slow conduction velocity and decreased maximum upstroke velocity with a decrease in sodium channel activation .