Beta-Adrenergic Signaling Induces Arrhythmias and Cardiac Dysfunction in Paclitaxel-Treated Mice

Abstract

In the past two decades, chemotherapy-related cardiac dysfunction (CRCD) has emerged as a dangerous complication in cancer survivors. Despite recent advancements, the mechanisms underlying the development and progression of CRCD remain poorly understood. Paclitaxel (PTX), an antimicrotubular agent, is known to produce dysrhythmia in 29% of patients when used as monotherapy. Since cardiac stress via β-adrenergic signaling is known to exacerbate arrhythmias, here we examine the action of a single isoproterenol (ISO) injection in wild-type mice treated with low and high therapeutic doses of PTX (8mg/kg and 12.5mg/kg, respectively). Male mice were treated with 4 intraperitoneal (IP) injections of PTX or vehicle (1:1:4 ratio of ethanol: Kolliphor: saline) per week for 4 weeks and a remote telemetry device was surgically implanted. Following treatment, mice were challenged with one IP injection of 5mg/kg ISO and ambulatory electrocardiography was performed. Over the course of PTX treatment, low- and high-dose PTX-treated mice displayed significant weight loss compared to vehicle-treated mice (-9.65% vs -0.52%, p=0.0018 and -10.99% vs 0.93%, p=0.0016, respectively). While low-dose PTX-treated mice did not show statistically significant differences in heart weight to body weight ratio compared to vehicle-treated mice (5.56mg/g vs 5.16mg/g, p=0.14), high-dose PTX-treated males showed increased cardiac hypertrophy compared to vehicle-treated mice (5.20mg/g vs 4.89mg/g, p=0.081). Prior to ISO challenge, there was no difference in arrhythmia severity between groups (0.0 vs 0.0, p=0.45 and 0.0 vs 1.0, p=0.99). One hour following ISO challenge, all mice treated with either a low or high dose of PTX showed higher arrhythmia severity than vehicle-treated mice (4.0 vs 2.5, p=0.0087 and 4.0 vs 3.0, p=0.0079, respectively). Additionally, low and high-dose PTX-treated mice experienced more atrioventricular block than vehicle-treated mice in the first hour following ISO challenge (9.17 vs 0.67, p=0.01 and 4.0 vs 1.0, p=0.06, respectively). After 24-hours, differences in arrhythmia severity returned to baseline (0.5 vs 1.0, p=0.99 and 1.0 vs 0.0, p=0.4). Our data indicates that chronic treatment of male mice with therapeutic levels of PTX predisposes to cardiac stress-induced atrial arrhythmias. This finding might have important implications for the treatment of CRCD. 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.