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Abstract
Background: Myocardial fibrosis is a key pathologic finding in the failing heart and is implicated as a cause of increased ventricular stiffness and susceptibility to ventricular arrhythmia. Neurohormonal mediators such as aldosterone and angiotensin II are known to cause fibrosis in experimental models, however, clinical evidence for the reversal of fibrosis with relevant antagonists is limited. Recent studies suggest that inflammatory mediators may contribute to fibrosis. In dilated cardiomyopathy the mechanism for myocardial fibrosis is unclear and its implications on systolic function are not known.Methods and Results: We studied the effect of a highly selective antagonist of SDF-1/CXCR4 signaling, AMD3100, on the development of cardiac fibrosis and cardiac function in mice with dilated cardiomyopathy due to cardiac-specific transgenic overexpression of the stress-kinase, Mst1. AMD3100 significantly attenuated the progression of myocardial fibrosis and this was accompanied by significant improvements in diastolic and systolic performance as evaluated in isolated Langendorff perfused hearts. AMD3100 reduced BNP mRNA expression but did not alter the expression of Ca2+ handling genes. CXCR4 antagonism also reduced the abundance of splenic CD4+ T cells.Conclusion: This study demonstrates that CXCR4 pathway contributes to pathogenesis of cardiac fibrosis in dilated cardiomyopathy, and it represents a new potential therapeutic target in heart failure. The data also demonstrate that anti-fibrotic strategies can improve systolic performance.
Highlights
Cardiac remodeling, incorporating structural, functional and molecular alterations are fundamental findings in the failing heart (HF)
Arising from the development of non-invasive tools to assess the extent of cardiac fibrosis using cardiac magnetic resonance imaging (Moon et al, 2006; Iles et al, 2008; Puntmann et al, 2016), it is evident that the extent of myocardial fibrosis is strongly associated with outcome in HF patients with reduced ejection fraction (HFREF) and those with preserved ejection fraction (HFPEF) (Iles et al, 2011; Mascherbauer et al, 2013)
In the present study we addressed the hypothesis that selective CXCR4 antagonism might prevent the development of myocardial fibrosis in an experimental model of dilated cardiomyopathy
Summary
Cardiac remodeling, incorporating structural, functional and molecular alterations are fundamental findings in the failing heart (HF). Individual patterns of remodeling, together with extra-cardiac abnormalities, contribute to the particular clinical phenotype. Myocardial fibrosis is a key pathologic finding in the failing heart and is implicated as a cause of increased ventricular stiffness and susceptibility to ventricular arrhythmia. Neurohormonal mediators such as aldosterone and angiotensin II are known to cause fibrosis in experimental models, clinical evidence for the reversal of fibrosis with relevant antagonists is limited. In dilated cardiomyopathy the mechanism for myocardial fibrosis is unclear and its implications on systolic function are not known
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