Novel Mechanisms of Anthracycline-Induced Cardiovascular Toxicity: A Focus on Thrombosis, Cardiac Atrophy, and Programmed Cell Death.

Silvio Antoniak,Brian C Jensen,Zhaokang Cheng,Sukanya Phungphong

doi:10.3389/fcvm.2021.817977

Abstract

Anthracycline antineoplastic agents such as doxorubicin are widely used and highly effective component of adjuvant chemotherapy for breast cancer and curative regimens for lymphomas, leukemias, and sarcomas. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that typically manifests as cardiomyopathy and can progress to the potentially fatal clinical syndrome of heart failure. Decades of pre-clinical research have explicated the complex and multifaceted mechanisms of anthracycline-induced cardiotoxicity. It is well-established that oxidative stress contributes to the pathobiology and recent work has elucidated important central roles for direct mitochondrial injury and iron overload. Here we focus instead on emerging aspects of anthracycline-induced cardiotoxicity that may have received less attention in other recent reviews: thrombosis, myocardial atrophy, and non-apoptotic programmed cell death.

Highlights

Considerable research effort has been invested in understanding the complex and multifactorial mechanisms underlying anthracycline-induced cardiotoxicity
Observational data suggest that some anti-cancer therapies are associated with increased risk for thrombotic events in the venous and arterial vasculature including deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (AT) as recently summarized by Anthracycline Cardiotoxicity: Thrombosis and Atrophy
With specific regard to anthracyclines, multiple myeloma patients were at an increased risk of DVT (16%) when doxorubicin (DOX) was added to thalidomide and that risk increased with age [6]

Summary

INTRODUCTION

Considerable research effort has been invested in understanding the complex and multifactorial mechanisms underlying anthracycline-induced cardiotoxicity. Longstanding evidence has established causative roles for oxidative stress in contributing to cardiomyocyte dysfunction and death [1]. Mitochondrial dysfunction generates much of this oxidative stress and the central role of multifaceted mitochondrial injury in anthracycline-induced cardiotoxicity has been comprehensively reviewed recently [2]. We will focus on emerging, though less-studied, mechanisms underlying the adverse effects of anthracyclines on both the heart and the vasculature

ANTHRACYCLINES AND THROMBOSIS

EFFECTS ON BLOOD FLOW AND THROMBUS FORMATION IN VIVO

ANTHRACYCLINES INDUCE MYOCARDIAL ATROPHY

CONTRIBUTIONS OF PROGRAMMED CELL DEATH TO ANTHRACYCLINE CARDIOTOXICITY

Findings

CONCLUSIONS