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

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…

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…

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