Abstract 4341: Dyssynchrony is a Prerequisite condition for Beta Reserve Upregulation By Cardiac Resynchronization Therapy

Abstract

Background Dyssynchronous Heart failure (DHF) versus synchronous is characterized by unique cellular and molecular substrates involving stress kinase and cell survival signaling ( Chakir et al. Circulation 2008 ; 117 : 1369 –77 ). Hypothesis The impact of CRT may depend upon whether there was a preceding dyssynchrony. Here, we tested such dyssynchrony dependence on basal and beta-adrenergic stimulated myocyte function in a canine HF model. Methods Adult dogs (n=8) underwent LBB radio-frequency ablation; half then subjected to atrial tachypacing-induced dyssynchronous HF (DHF) for 6wks, while the others had 3 weeks DHF followed by 3-wks bi-ventricular tachypacing (CRT). 5 additional dogs were subjected to RV freewall tachypacing for 3wks (dyssynchrony) followed by 3 weeks right atrial tachypacing (resynchronization; V3A3), and 3 more were subjected to synchronous heart failure (RA tachypacing for 6 wks; A6). 3 non-paced dogs served as controls. Myocytes were enzymatically isolated from the LV free wall and field stimulated in a perfusion chamber. Sarcomere shortening and calcium transient were determined with and without 10 −7 M isoproterenol. Results: DHF, V3A3, A6 and CRT hearts had similar global failure, with dP/dtmax 1190.2±139.8 vs. 1111.8±131.6 vs. 1333.0±205.2 vs. 1195.3±137.6 mmHg/s, respectively (1900.3±176.8 in control). However, there were marked differences in basal and β-stimulated myocyte calcium transients and sarcomere shortening (Table , n=8 –30 cells/ group). Intriguingly, both DHF and A6 cells had reduced basal and β-AR stimulated sarcomere shortening and Ca transients versus control. In contrast, both V3A3 and CRT displayed enhanced rest and β-AR responses. Conclusion: HF resynchronization improves rest and β-AR cellular function over those never dyssynchronous. A particular substrate develops with DHF that when offset by CRT enhances cellular function beyond that with synchronous HF; explaining the CRT impact in targeted patients.