Abstract 4146080: Depolymerization of Myocyte Microtubules with Colchicine Normalizes Increased Left Ventricular Chamber Stiffness Induced by Brief Repetitive Pressure Overload

Objective: Swine subjected to brief (30-min) episodes of repetitive pressure overload (BRPO) exhibit increased left ventricular (LV) chamber stiffness in the absence of anatomic hypertrophy or increased interstitial fibrosis. We employed acute colchicine administration to determine the role of microtubule remodeling in this process. Methods: We used daily 30-minute infusions of phenylephrine (PE; 400µg/min, n=12) to induce BRPO. This raised LV systolic pressure from 102 ± 4 to 215 ± 14 mmHg and LVEDP from 12.5 ± 2.3 to 30.0 ± 1.8 mmHg. Serial LV chamber stiffness (ΔLVEDP / ΔLVEDV) was determined using echocardiography and LVEDP at rest and during PE-induced preload elevation (n=7). We assessed the contribution of microtubules to stiffness 1-hour after colchicine (1mg/kg iv). Results: Two-weeks of BRPO produced a significant increase in LV stiffness (Figure). Pathological analysis (n=5) demonstrated that this was associated with increased microtubule detyrosination (from 15.9 ± 1.7% to 21.9 ± 1.1% of myocyte area; p <0.05) but no increase in interstitial fibrosis (5.03 ± 0.33% vs. 4.99 ± 0.34%, p=0.95). Serial studies of LV chamber stiffness showed an increase from 0.43 ± 0.08 mmHg/mL at baseline to 0.86 ± 0.08 mmHg/mL after 2-weeks of BRPO (p<0.01). After colchicine, LV stiffness decreased to 0.54 ± 0.04 mmHg/mL (n=7, p<0.01) and was not significantly different from baseline values before BRPO. Conclusions: Acute depolymerization of microtubules with colchicine reduces the increased LV chamber stiffness after BRPO to near baseline levels. These data indicate that myocyte microtubular remodeling is a major determinant of LV chamber stiffness arising from BRPO and contributes to diastolic LV properties in this model, which may pose relevance in some forms of hypertensive HFpEF.