Radiotherapy-induced heart disease: a review of the literature

Abstract

Radiotherapy as one of the four pillars of cancer therapy plays a critical role in the multimodal treatment of thoracic cancers. Due to significant improvements in overall cancer survival, radiotherapy-induced heart disease (RIHD) has become an increasingly recognized adverse reaction which contributes to major radiation-associated toxicities including non-malignant death. This is especially relevant for patients suffering from diseases with excellent prognosis such as breast cancer or Hodgkin's lymphoma, since RIHD may occur decades after radiotherapy. Preclinical studies have enriched our knowledge of many potential mechanisms by which thoracic radiotherapy induces heart injury. Epidemiological findings in humans reveal that irradiation might increase the risk of cardiac disease at even lower doses than previously assumed. Recent preclinical studies have identified non-invasive methods for evaluation of RIHD. Furthermore, potential options preventing or at least attenuating RIHD have been developed. Ongoing research may enrich our limited knowledge about biological mechanisms of RIHD, identify non-invasive early detection biomarkers and investigate potential treatment options that might attenuate or prevent these unwanted side effects. Here, we present a comprehensive review about the published literature regarding clinical manifestation and pathological alterations in RIHD. Biological mechanisms and treatment options are outlined, and challenges in RIHD treatment are summarized.

Keywords: Radiotherapy; cancer treatment; heart injury; radiation-induced heart injury; thoracic cancer.

Figure 1

Putative pathway overview how radiation therapy is involved in the development of cardiac fibrosis upon thoracic radiotherapy for cancer. RT, radiation therapy; PPA, protein phosphatase; AKT, protein kinase B; TGF-β, transforming growth factor beta; PIP2, phosphatidylinositol Biphosphate; PI3K, phosphoinositide 3-kinases; ROS, reactive oxygen species; ERK, extracellular signal-regulated kinase; TAK, TGF-β-activated kinase; MKK, mitogen-activated protein kinase kinase; JNK, the c-Jun NH2-terminal protein kinase; ATF, activating transcriptional factor; CTGF, connective tissue growth factor; α-SMA, α smooth muscle actin; Ang II, angiotensin II; AMPKα, AMP-activated protein kinase α; MAPK, mitogen-activated protein kinase; P38, P³⁸ mitogen-activated protein kinase; JIP, JNK-interacting protein; AP-1, activating protein-1; CCN, the first number of CYR61, CTGF & NOV family; IL, interleukin; INF-α, interferon-α; RhoA, Ras homolog gene family, member A; ROCK, Rho-associated protein kinase; MRTF, myocardin-related transcription factor; YAP, yes-associated protein; PLC-2, Phospholipase C 2; PkD, Protein kinase D; PKC, Protein kinase C; SRF, serum response factor; C/EBPβ, CCAAT-enhancer-binding protein β; VEGFR, vascular endothelial growth factor receptors; NF-κB, nuclear factor-κB; COX-2, cyclooxygenase-2; TNF-α, tumour necrosis factor alpha; IKK, NF-κB kinase; MMPs, matrix metallopeptidases; ECM, extracellular matrix; Activate.