Abstract P3076: Immune Checkpoint Regulator Impairs Left Ventricular Remodeling In A Hypertension-Fibrosis Model Of Cardiac Injury.

Abstract

Cancer treatments directly result in cardiovascular toxicity and may exacerbate typical age-related diseases such as hypertension and diabetes. Among cancer treatments contributing to survivorship, immunotherapies including immune checkpoint inhibitors (ICIs) are now widely utilized due to their groundbreaking efficacy. CD40 agonist (CD40ag) antibodies are immune checkpoint regulators that have emerged as promising candidates with remarkable efficacy across tumors including those thought to be resistant to established ICIs. To investigate CD40 signaling and its potential for adverse left ventricular remodeling in a hypertensive-fibrosis model of cardiac injury, C57BL/6J mice were pretreated with isotype or CD40ag antibodies 7 days prior to myocardial injury, then continued for a total of 35 days. Myocardial injury was induced by continuous infusion of angiotensin II and phenylephrine (AngII/PE) for 4 weeks. Masson’s trichrome stain revealed increased fibrosis and immunohistochemistry demonstrated increased immune cell abundance in heart sections. There was impaired cardiac function assessed by 2-D echocardiography in minimally sedated mice showing reduced ejection fraction and radial strain. Finally, CD40 agonism resulted in gene expression upregulation of multiple inflammatory cytokines and chemokines post-cardiac injury. These results reveal that pre-treatment with CD40 agonist prior to injury with AngII/PE infusion increased myocardial inflammation and impaired left ventricular remodeling.