Novel Therapeutic Targets in the Management of Atrial Fibrillation
Novel Therapeutic Targets in the Management of Atrial Fibrillation
Considering the central role of TGF-β1 as a mediator of atrial fibrosis, it is intuitive to believe that anti-TGF-β1 therapies could be potentially useful to inhibit atrial fibrosis and hence prevent the development of AF. Pirfenidone, 5-methyl-1-phenyl-2 (1H)-pyridone, was investigated by Lee et al. in a VTP-induced CHF canine model. Induction of CHF was found to be associated with increased degree of atrial fibrosis and atrial conduction heterogeneity as compared with controls, whereas the treatment with pirfenidone resulted in decreased atrial fibrosis, conduction heterogeneity and hence reduced AF vulnerability. Furthermore, pirfenidone was also found to reduce the TGF-β1-mediated downstream expression of various MAP kinases studied on cytokine profile in this study. Treatment with pirfenidone was also observed to be associated with a decrease in MMP-9 and tissue inhibitor of metalloproteinase-4 levels, further supporting its potential as an antifibrotic agent. Yamazaki et al. also demonstrated the beneficial effects of pirfenidone in an Ang II-mediated cardiac hypertrophy model in mice and demonstrated its efficacy in mitigating Ang II-mediated perivascular and interstitial fibrosis and TGF-β1 expression; additionally, pirfenidone also attenuated the expression of mineralocorticoid receptors. Various other models investigating pulmonary fibrosis have also studied the antifibrotic role of pirfenidone. In the future, more robust pre-clinical and clinical studies are likely to help clarify the relevance of pirfenidone as a novel agent for prevention of AF ( Table 2 ).
Recent investigations by Barter et al. have also identified histone deacetylases (HDACs) as regulatory mediators of the profibrotic function of TGF-β1 at the gene-expression level. Several genes (such as smad2, 3 and 7) which regulate matrix turnover in response to TGF-β1 are selectively regulated by HDACs. Selective inhibition of HDACs was demonstrated to suppress the induction of profibrotic signals (disintegrin and metalloproteinase-12) which are driven by TGF-β1. In addition, Liu et al. showed that global HDAC inhibition could reverse atrial fibrosis and inducible atrial arrhythmias. In this study, mice that were ~3 months old already had established atrial fibrosis and inducible atrial arrhythmias. After treatment with the global HDAC inhibitor trichostatin A daily for 2 weeks, the percentage of atrial fibrosis and arrhythmia burden were reduced in the experimental group when compared with wild-type littermate mice. Interestingly, the degree of ventricular hypertrophy and diastolic dysfunction were not affected by the HDAC inhibitor, but along with a reduction in atrial fibrosis, there was an increase in Cx40 gap junctions in the atrium of mice treated with HDAC inhibitor. These observations support the role of HDACs as key mediators of profibrotic proliferation signal in fibroblasts which are activated by TGF-β1.
While it is intuitive to be optimistic about the role of antifibrotic therapy in AF, it is also important to be cognizant about the limitations of the role of atrial fibrosis in pathogenesis of AF. There is also a further need to better understand the relationship between the extent of atrial fibrosis and the threshold for AF initiation. Knowledge of a precise mechanism by which atrial fibrosis leads to conduction heterogeneity and development of AF will help clarify whether atrial fibrosis is the central event in the pathogenesis of AF.
Therapeutic Interventions on TGF-β1
Considering the central role of TGF-β1 as a mediator of atrial fibrosis, it is intuitive to believe that anti-TGF-β1 therapies could be potentially useful to inhibit atrial fibrosis and hence prevent the development of AF. Pirfenidone, 5-methyl-1-phenyl-2 (1H)-pyridone, was investigated by Lee et al. in a VTP-induced CHF canine model. Induction of CHF was found to be associated with increased degree of atrial fibrosis and atrial conduction heterogeneity as compared with controls, whereas the treatment with pirfenidone resulted in decreased atrial fibrosis, conduction heterogeneity and hence reduced AF vulnerability. Furthermore, pirfenidone was also found to reduce the TGF-β1-mediated downstream expression of various MAP kinases studied on cytokine profile in this study. Treatment with pirfenidone was also observed to be associated with a decrease in MMP-9 and tissue inhibitor of metalloproteinase-4 levels, further supporting its potential as an antifibrotic agent. Yamazaki et al. also demonstrated the beneficial effects of pirfenidone in an Ang II-mediated cardiac hypertrophy model in mice and demonstrated its efficacy in mitigating Ang II-mediated perivascular and interstitial fibrosis and TGF-β1 expression; additionally, pirfenidone also attenuated the expression of mineralocorticoid receptors. Various other models investigating pulmonary fibrosis have also studied the antifibrotic role of pirfenidone. In the future, more robust pre-clinical and clinical studies are likely to help clarify the relevance of pirfenidone as a novel agent for prevention of AF ( Table 2 ).
Recent investigations by Barter et al. have also identified histone deacetylases (HDACs) as regulatory mediators of the profibrotic function of TGF-β1 at the gene-expression level. Several genes (such as smad2, 3 and 7) which regulate matrix turnover in response to TGF-β1 are selectively regulated by HDACs. Selective inhibition of HDACs was demonstrated to suppress the induction of profibrotic signals (disintegrin and metalloproteinase-12) which are driven by TGF-β1. In addition, Liu et al. showed that global HDAC inhibition could reverse atrial fibrosis and inducible atrial arrhythmias. In this study, mice that were ~3 months old already had established atrial fibrosis and inducible atrial arrhythmias. After treatment with the global HDAC inhibitor trichostatin A daily for 2 weeks, the percentage of atrial fibrosis and arrhythmia burden were reduced in the experimental group when compared with wild-type littermate mice. Interestingly, the degree of ventricular hypertrophy and diastolic dysfunction were not affected by the HDAC inhibitor, but along with a reduction in atrial fibrosis, there was an increase in Cx40 gap junctions in the atrium of mice treated with HDAC inhibitor. These observations support the role of HDACs as key mediators of profibrotic proliferation signal in fibroblasts which are activated by TGF-β1.
While it is intuitive to be optimistic about the role of antifibrotic therapy in AF, it is also important to be cognizant about the limitations of the role of atrial fibrosis in pathogenesis of AF. There is also a further need to better understand the relationship between the extent of atrial fibrosis and the threshold for AF initiation. Knowledge of a precise mechanism by which atrial fibrosis leads to conduction heterogeneity and development of AF will help clarify whether atrial fibrosis is the central event in the pathogenesis of AF.
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