Abstract 358: Pacemaker Induced Transient Asynchrony (PITA) Restores Contractile Reserve in Synchronous Heart Failure

Abstract

Heart failure (HF) with dyssynchrony treated with biventricular pacing (CRT) displays enhanced global and cellular function even compared to always synchronous HF. This suggests while HF is worsened by sustained dyssynchrony, it may paradoxically be improved by brief periods of Pacemaker Induced Transient Asynchrony (PITA). We tested this hypothesis in dogs tachypaced for 6 wks to induce HF. The HF group received atrial pacing and was compared to PITA (atrial pacing during day; right ventricular pacing, producing dyssynchrony, from 0000-0600). PITA blunted dilation (end diastolic and end systolic volumes reduced by 11 and 19%, respectively), reduced end-diastolic pressures from 22 to 13 mmHg, and improved the contractile response to dobutamine by 29%. Myocyte sarcomere shortening and calcium transient amplitude were depressed in HF and little improved by β adrenergic (βA) stimulation. PITA improved baseline function slightly, but virtually restored βA stimulated reserve. Membrane βA receptor density increased with PITA by 36% as well. Another contributor to the change in functional reserve was found in myofilament maximal calcium activated force (Fmax) normalized to cell cross sectional area (CSA). This declined ~40% in HF vs. Control, but was fully restored by PITA. However, as CSA was greater in HF and normalized by PITA, raw Fmax was similar despite hypertrophy in HF, suggesting HF myocytes had dysfunctional myofilaments, which PITA prevented. Electron microscopy confirmed normal myofilament structure in Control and PITA, whereas 40% of HF sarcomeres displayed deteriorated z-disks and loss of normal registration of the thick and thin filaments. In HF, 39% of HF isolated myofibrils produced virtually zero maximal force, whereas Control and PITA fibers functioned normally. Thus, there are two populations of myofibrils within HF hypertrophied cells, with ~40% structurally and functionally disrupted. PITA reverses this to restore force-calcium activation and with improved βA receptor signaling, restores functional reserve, suppressing chronic maladaptive remodeling. This surprising finding indicates PITA can ameliorate HF pathobiology and improve reserve function. Further studies are needed to test if such benefits translate to humans.