Arrhythmogenic structural remodeling : novel insights into consequences, determinants and therapeutic potential

Atrial fibrillation (AF) remains the most encountered arrhythmia in clinical practice and a major cause of morbidity and mortality. Electrical, contractile and structural remodeling are important synergistic contributors to the AF substrate. Fibrosis is a hallmark of arrhythmogenic structural remodeling and occurs as a convergent pathological end-point in a variety of settings. The consequences and determinants of fibrotic structural remodeling are presently poorly understood. The overall purpose of these studies was to gain insights into the mechanisms governing the development and consequences of fibrosis, as well as the potential therapeutic value of fibrosis-targeting interventions.We have shown previously that structural remodeling in experimental congestive heart failure (CHF) is quantitatively different (∼20-fold greater) in atria compared to ventricles. To better understand the regional differences in fibrotic remodeling, we examined the hypothesis that there exist intrinsic differences between atrial and ventricular fibroblasts. Despite phenotypic similarity, cultured atrial fibroblasts were found to be consistently more reactive than ventricular, showing distinct growth characteristics, proliferative responses, and gene-expression profiles. PDGF-related differences played an important role in atrial-ventricular proliferative response discrepancies, and appear to be similarly implicated in vivo.Atrial fibrosis commonly accompanies AF, but whether the fibrosis is a cause of AF or can be caused by rapid atrial activation is unclear. We therefore addressed the hypothesis that rapid-pacing of cardiomyocytes can influence fibroblast proliferation and secretory functions in a paracrine fashion. Cultured fibroblasts were incubated with the conditioned medium from tachypaced atrial cardiomyocytes. Tachypacing-conditioned medium induced differentiation to an activated secretory myofibroblast phenotype. Fibrosis-related genes were similarly increased in a clinically-relevant experimental model of atrial-tachypacing (ATP)-induced AF, providing evidence for consequences of this potential paracrine mechanism.It is unclear precisely how fibrosis interferes with conduction. Myocardial electrical continuity is maintained by specialized gap junction proteins connexin43 (Cx43) and connexin40 (Cx40), and changes in connexin expression, phosphorylation and localization are thought to correlate with the onset of fibrosis and pro-arrhythmic conduction slowing. We sought to determine the relative contributions of fibrosis and connexin changes to the AF substrate during the development and reversal of experimental CHF. Atrial fibrous tissue content was found to be increased in CHF without reversal, correlating with the persistence of conduction abnormalities and prolonged AF duration in the recovery period. CHF did not produce significant changes in atrial Cx43 and Cx40 localization or mRNA and protein expression. Cx43 was however, hypo-phosphorylated in CHF with complete reversal during recovery, suggesting that fibrosis over connexin changes is the primary contributor to AF maintenance in experimental CHF.Finally, we undertook studies to determine if fibrosis can be attenuated pharmacologically in two in vivo models of structural remodeling. Numerous studies have described cardioprotective effects of resveratrol (antioxidant, anti-inflammatory, anti-fibrotic), thus providing a strong rationale to hypothesize that resveratrol administration would ameliorate the progression of remodeling and loss of contractility which results from myocardial infarction (MI). Serial echocardiography and dobutamine stress testing revealed that resveratrol did not improve cardiac remodeling or global hemodynamic function up to 12 weeks post-MI, but did preserve cardiac contractile reserve. We then similarly evaluated the effects of two lipid-lowering agents, simvastatin and fenofibrate, on atrial fibrosis development in experimental CHF and on cultured atrial fibroblasts. Simvastatin but not fenofibrate attenuated atrial fibrosis, conduction heterogeneity and hemodynamic changes. We observed statin-induced direct inhibition of profibrotic atrial fibroblast responses which may constitute a novel mechanism for preventing the CHF-induced fibrotic AF substrate.Our findings highlight the contribution of irreversible structural remodeling in AF maintenance. Results indicating that AF per se can promote atrial fibrosis underscore the importance of normalizing cardiac rhythm to prevent this outcome, particularly in light of evidence demonstrating atrial sensitivity to fibrotic change. This work is relevant to designing improved strategies for preventing arrhythmogenic structural remodeling, and has revealed novel and potentially promising therapeutic avenues