Abstract 2730: NCX is a Target of Focally Mediated Arrhythmias During Early Hypertrophic Remodeling
Background: The majority of sudden cardiac deaths occur at relatively early stages of disease development before clear signs of LV dysfunction. Here, we investigate the nature and mechanistic underpinnings of triggered arrhythmias during early hypertrophic remodeling.
Methods and Results: In a rat model of concentric LV hypertrophy (LVH) produced by ascending aortic banding, we investigate the presence of triggered activity and identify the nature of arrhythmias using high resolution optical action potential imaging of ex vivo perfused hearts. Molecular correlates were investigated by measuring the expression of key calcium handling proteins at time points reflecting low, moderate, and severe mortality rates in vivo. Closely coupled action potentials consistent with afterdepolarization mediated triggered beats were readily observed in 6/15 LVH hearts. Similarly, LVH (8/15) but not controls exhibited sustained episodes of VT following rapid stimulation. Arrhythmias were observed at time points when LV function measured in vivo using echocardiography and in vitro using a sarcomere shortening assay were preserved. The initiation and early maintenance of these arrhythmias were formed by rapid and highly uniform activation wavefronts (20.4±4.1Hz) emanating from focal sites distal to the former site of stimulation and were independent of conduction slowing. In contrast, APD50 and 90 in LVH hearts were significantly (p < 0.01) prolonged by > 30% and 90%, respectively over controls. Western blot analysis revealed a major (by > 30%) upregulation in the density of the alpha subunit of the Na-Ca exchanger (NCX1) with no change in SERCA2a or phospholamban expression in 4 week LVH animals. Treatment of LVH hearts with the NCX blocker (KB-R7943, 10uM) shortened APD50 by 28.9% and APD90 by 52.8% during baseline pacing (4Hz), blunted steady-state APD restitution over a wide range of pacing rates (3– 8Hz), and partially suppressed the induction of VT following rapid stimulation.
Conclusion: Remodeling during early progression of LVH predisposes to triggers and focally mediated arrhythmias secondary to increased NCX1 expression. These findings highlight NCX as an important target for suppressing focally mediated arrhythmias prior to LV dysfunction.
This research has received full or partial funding support from the American Heart Association, National Center.