Microtubules distinctly contribute to the performance of the healthy and pressure-overloaded RV

Introduction: Microtubules (MT) are a key contributor to cardiomyocyte contractility and mechanics. Recently, our group reported that acute depolymerization of MT reduces viscosity and elasticity and alters anisotropy of healthy and pressure-overloaded right ventricular (RV) tissues. While RV free wall viscosity and elasticity are distinctly upregulated with chronic pressure overload, how organ function is affected by viscoelastic contribution of the MT remains unknown. Our aim was to investigate the role of MT polymerization in RV function from its effect on RV tissue viscoelasticity. We hypothesized that the MT differentially contributes to healthy and pressure-overloaded RV function. Methods: All procedures and methods were approved by Colorado State University IACUC. Pulmonary hypertension (PH) was induced in 6-week-old male rats via 3-week monocrotaline treatment. Healthy age- and sex-matched rats served as control. Pressure-volume (PV) relationships were obtained by RV catheterization before and after intramyocardial injections of 0.3mM colchicine (COL) to acutely depolymerize the MT network and reduce tissue viscoelasticity. Functional impacts were evaluated by monitoring changes in RV end-systolic pressure (ESP), cardiac output (CO), stroke volume (SV), ejection fraction (EF), dP/dt max and min, cardiac effciency (CE), and the end-systolic pressure-volume relation (ESPVR). Results: As expected, monocrotaline treatment induced marked PH and RV contractile dysfunction, indicated by a significant elevation of RV ESP with reduced CO and ESPVR. In the healthy RV, COL treatment led to marked reductions in all functional parameters, indicating that the MT network is critical to maintain RV performance and contractile function in the healthy heart. In the pressure-overloaded RV, COL treatment similarly reduced SV, CO, EF, and dP/dt max and min, but increased CE and ESPVR, indicating that MT depolymerization improved mechanical effciency and contractility. To rule out effects caused by bolus injections alone, we administered a similar quantity of saline and observed no effects on the PV parameters in healthy RV. Discussion: Our study is the first to investigate the acute effect of MT depolymerization on RV function in healthy and diseased states. We found distinct contributions of MT to the contractile function and mechanical effciency of healthy and pressure-overloaded RVs. These findings reveal a critical influence of tissue viscoelasticity on RV physiology and dysfunction, emphasizing the importance of considering myocardial viscoelastic behavior in future studies investigating cardiac remodeling and heart failure pathophysiology. This work is partially supported by the National Science Foundation (NSF) grant 2244994. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.