Pathomechanisms and therapeutic opportunities in radiation-induced heart disease: from bench to bedside

Abstract

Cancer management has undergone significant improvements, which led to increased long-term survival rates among cancer patients. Radiotherapy (RT) has an important role in the treatment of thoracic tumors, including breast, lung, and esophageal cancer, or Hodgkin's lymphoma. RT aims to kill tumor cells; however, it may have deleterious side effects on the surrounding normal tissues. The syndrome of unwanted cardiovascular adverse effects of thoracic RT is termed radiation-induced heart disease (RIHD), and the risk of developing RIHD is a critical concern in current oncology practice. Premature ischemic heart disease, cardiomyopathy, heart failure, valve abnormalities, and electrical conduct defects are common forms of RIHD. The underlying mechanisms of RIHD are still not entirely clear, and specific therapeutic interventions are missing. In this review, we focus on the molecular pathomechanisms of acute and chronic RIHD and propose preventive measures and possible pharmacological strategies to minimize the burden of RIHD.

Keywords: Molecular pathomechanisms of radiation-induced heart disease; Onco-cardiology; Prevention and therapy of radiation-induced heart disease; Radiation heart sequelae.

Fig. 1

Possible clinical manifestations of RIHD. RIHD is a progressive disease that covers a broad spectrum of cardiac pathology. RIHD may manifest as acute or chronic pericarditis, conduction system abnormalities, ischemic heart disease, cardiomyopathy, heart failure including HFpEF and HFrEF, or valvular heart disease, according to the site of damage. LAD left descending coronary artery, LVH left ventricular hypertrophy, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction

Fig. 2

Putative mechanisms in the acute phase of RIHD and potential pharmacological interventions. RT could induce immediate oxidative/nitrosative/nitrative damage of macromolecules, including DNA, proteins, and lipids, in all cardiac cell types. The increased oxidative/nitrative/nitrosative stress triggers other biological processes, including acute inflammation, and cell death forms in the acute phase of RIHD in the different cell types. Parallel, hypertrophic, and fibrotic gene programs start in the surviving cardiomyocytes as compensatory mechanisms. Potential preventive and therapeutic pharmacologic agents are depicted in green boxes targeting different molecular mechanisms. ACEi angiotensin-converting enzyme inhibitors, Ac-SDKP N-acetyl-Ser-Asp-Lys-Pro, ARB angiotensin receptor blockers, α-SMA α-smooth muscle actin, ATP adenosine triphosphate, Ca²⁺ calcium ion, Col collagen, CTGF connective tissue growth factor, CytC cytochrome C, ERS endoplasmic reticulum stress, FGF fibroblast growth factor, GHRH growth hormone-releasing hormone, ICAM intercellular adhesion molecules, IL interleukin, JNK c-Jun N-terminal kinases, ly lymphocyte, ma macrophage, MAPK mitogen-activated protein kinase, miR microRNA, mo monocyte, Mito mitochondrion, NF-κB nuclear factor-κB, ng neutrophil granulocyte, NO nitric oxide, PACAP38 pituitary adenylate cyclase-activating polypeptide 38, PARP1poly-ADP-ribose-polymerase 1, PECAM platelet endothelial cell adhesion molecule, rhNRG-1β recombinant human neuregulin-1β, ROS/RNS reactive oxygen and nitrogen species, RT radiotherapy, TGF-β tissue growth factor-β, TNF-α tumor necrosis factor- α, VCAM vascular cell adhesion molecule

Fig. 3

Putative mechanisms in the chronic phase of RIHD and potential pharmacological interventions. Several pathomechanisms in the chronic phase of RIHD including oxidative/nitrative/nitrosative stress, cell death, and inflammatory processes, overlap during the acute and chronic phases of RIHD. These mechanisms could activate and potentiate each other in the different cardiac cell types leading to a vicious cycle. In the early chronic phase of RIHD, compensatory mechanisms including manifest left ventricular hypertrophy and endothelial cell proliferation are predominant. If these compensatory mechanisms are exhausted, fibrosis and endothelial senescence play the central role in the late phase of disease progression. The exact molecular transition points from acute to compensated and decompensated chronic forms of RIHD are unknown yet. Potential preventive and therapeutic pharmacologic agents are depicted in green boxes targeting different molecular mechanisms. ACEi angiotensin-converting enzyme inhibitors, ARB angiotensin receptor blockers, α-SMA α-smooth muscle actin, ATP adenosine triphosphate, Ca²⁺ calcium ion, CaMK Ca²⁺/calmodulin-dependent protein kinase, CKD chronic kidney disease, Col collagen, CTGF connective tissue growth factor, CytC cytochrome C, CV cardiovascular, ERS endoplasmic reticulum stress, ETC electron transport chain, FGF fibroblast growth factor, GHRH growth hormone-releasing hormone, JNK c-Jun N-terminal kinases, ly lymphocyte, ma macrophage, MAPK mitogen-activated protein kinase, miR microRNA, mo monocyte, Mito mitochondrion, NF-κB nuclear factor-κB, ng neutrophil granulocyte, PACAP38 pituitary adenylate cyclase-activating polypeptide 38, PARP1 poly-ADP-ribose-polymerase 1, PECAM platelet endothelial cell adhesion molecule, ROS/RNS reactive oxygen and nitrogen species, TGF-β tissue growth factor-β, TNF-α tumor necrosis factor-α

Fig. 4

Algorithm of cardiovascular follow-up after thoracic RT. CAD coronary artery disease, ECG electrocardiography, echo: echocardiography, HER2 human epidermal growth factor receptor, LAD left anterior descending artery, RT radiotherapy