Effect of Cardiac Resynchronization Therapy on Myocardial Fibrosis and Relevant Cytokines in a Canine Model With Experimental Heart Failure

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Cardiac resynchronization therapy (CRT) is an established treatment for patients with refractory heart failure (HF), severe left ventricular (LV) dysfunction, and conduction disorders, especially in the form of left bundle branch block (LBBB). Since then most attention has been focused on how to improve CRT response rate. Meanwhile, recent studies have begun exploring how CRT impacts the failing heart at the cellular and molecular level. As is verified in previous studies, CRT reverses cardiac autonomic remodeling by upregulating presynaptic receptor function, attenuates the regional heterogeneity of action potential duration by restoring ion channel remodeling and abnormal Ca2+ homeostasis, regulates contractile function by increasing α‐myosin heavy chain (MHC) and SERCA2a/phospholamban (PLB) expressions, and reduces apoptotic and inflammatory cytokines.1
Structural remodeling of the failing myocardium can bring about cardiomyocyte loss, interstitial collagen and extracelluar matrix (ECM) deposit, leading to cardiac fibrosis, a hallmark of end‐stage chronic HF (CHF). The excess of fibroblast proliferation and ECM formation results from the upregulation of several cytokines and neurohormones. Transforming growth factor (TGF)‐β signaling pathway is a key mediator in the pathogenesis of ventricular remodeling via induction of interstitial fibrosis. A member of the TGF‐β family, TGF‐β1, is a profibrotic cytokine that stimulates the production of ECM proteins in the heart. Administration of an anti‐TGF‐β1 neutralizing antibody prevents myocardial fibrosis and cardiac dysfunction in pressure‐overloaded rat hearts.5 Osteopontin (OPN), a newly identified determinant of ECM turnover and composition, has been proved to be essential for TGF‐β1‐induced myofibroblast differentiation and activation, which directly regulates collagen‐I deposition.6 Recent studies demonstrated that CRT‐induced LV reverse remodeling was associated with a decreased plasma level of TGF‐β1 and OPN. Preimplant circulating TGF‐β1 and OPN may even represent an indicator of CRT response.4 However, it remains unknown whether the reverse remodeling following CRT is accompanied by attenuation of these corresponding mediators in myocardial tissues. In the present study, we investigated the expression of cytokines concerning myocardial fibrosis in a canine model of LV dysfunction with dyssynchrony and the potential benefits of CRT. We hypothesize that by means of coordinating impaired electrical activation and myocardial contraction, CRT could also impact on molecules regarding myocardial fibrosis, thus promoting LV reverse remodeling.

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