Abstract 3178: Regional and Global Reverse Molecular Remodeling from Cardiac Resynchronization Therapy Despite Persistent Heart Failure In the Dog
Cardiac dyssynchrony impairs global ventricular function and efficiency, and triggers regional molecular polarization in the high stress late-contracting wall. Cardiac resynchronization therapy (CRT) improves mechanoenergetics, but its impact on global and/or global molecular signaling is largely unknown. Adult dogs (n=12) underwent left bundle branch radio-frequency ablation (QRS duration increased from 50±7 to 104±7 ms); half subjected to RA pacing-induced dyssynchronous heart failure (DHF) for 6 weeks, and the other half to RA tachypacing-induced DHF for 3 weeks followed by 3 weeks of bi-ventricular CRT, employing the same tachypacing rate (190–200 bpm). CRT led to a marked rise in a synchrony index (59.0±9.3 vs 37.4±5.2 in DHF dogs), but had similar LV chamber dilation, and reduced ejection fraction and dP/dtmax. Molecular signaling in anterior and lateral walls revealed two distinct patterns. TNF alpha, p38, ERK, and JNK MAP-kinases, and CamKII were disproportionately expressed in the late-activated wall in DHF dogs consistent with elevated stress. These became more homogenous across the ventricle with CRT. Other enzymatic changes, however, were global in nature. With DHF, activated Akt, and downstream kinase p70s6K, phospho-BAD were all reduced, and PARP cleavage and Caspase 3 activation enhanced. These changes were globally reversed in CRT animals. These data reveal potent influences of resynchronization on regional as well as global reverse molecular remodeling despite the persistence of overall failure. The changes suggest mechanisms to enhance cell survival, and reduce heterogeneity of regional stress-kinase changes that could otherwise contribute to underlying cardiac dysfunction and instability.