Abstract 622: Load-Independent Systolic Dysfunction and Altered Z-Disc Protein Phosphorylation in Swine with Stretch-Induced Myocardial Stunning

Abstract

Objective: We recently demonstrated that a transient rise in left ventricular (LV) preload leads to a reversible reduction in LV ejection fraction in the absence of ischemia (“stretch-induced stunning”). The present study was designed to determine whether this phenomenon is characterized by impaired load independent LV systolic function and alterations in sarcomeric protein phosphorylation. Methods: Swine (n=9) received a 1 hour infusion of phenylephrine (PE; 18 mg/hour iv) to transiently elevate LV end-diastolic pressure (EDP). Load independent systolic function was derived from LV pressure volume loops collected during inferior vena cava occlusion at baseline and 30 min after PE (Transonic SciSense). In a subset of animals (n=5), LV tissue was collected 1 hour after PE for TMT-labeled, LC-MS-based quantitative phosphoproteomics using Orbitrap. Results: PE elicited a rise in LV EDP (9±2 to 29±3 mmHg, p<0.01), followed by a reduction in LV ejection fraction and LV dP/dt max 30 min later. At this time, load independent indices of LV systolic function tended to exhibit a reduced slope with a significant rightward shift of the volume-axis intercept (V 0 ), indicative of decreased contractility ( Table ). This was accompanied by altered phosphorylation of 16 sarcomeric Z disc proteins at 27 phosphosites, including increased phosphorylation of α actinin, α crystallin B chain, desmin, and myotilin. Conclusions: Stretch-induced stunning following transient preload elevation is characterized by load independent systolic dysfunction. Phosphoproteomics implicate alterations in Z disc protein phosphorylation as a mechanism underlying contractile dysfunction in this condition.