Behdokht Fathi Dizaji,1,*
1. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Cardio-oncology is a multidisciplinary field, established to find and manage patients (prevention, diagnosis, and treatment) with adverse cardiovascular effects of anticancer treatments. For the first time, cardiotoxicity of thoracic radiation was described in patients who exhibited pathological alternations in their myocardium. Both traditional cancer therapies including chemotherapies, radiation and new treatments like targeted therapies via monoclonal antibodies, kinase inhibitors and immune checkpoint inhibitors, have demonstrated mild to severe cardiovascular complications.
Methods: This review provides a summarized overview of pathophysiology and genetic base of cardio-oncology discipline through searching databases, PubMed and Scopus.
Results: Pathophysiology
Cancer therapies affect the interaction between cancer and the endothelium, resulting in vascular and metabolic perturbations. Cardiotoxicity is the most serious side effect of chemotherapy. Anthracyclines are used to treat patients with different childhood and adult-onset cancers. They cause cardiotoxicity in a dose-dependent manner in some patients. cardiomyopathy process initiates with single-cell myocytolysis and finally leads to disruption of myocardial structure and heart failure. Various mechanisms are proposed comprising, oxidative stress, mitochondrial injury, topoisomerase 2-ß, impaired DNA synthesis, deregulated gene expression, inhibited calcium release from the sarcoplasmic reticulum, defective mitochondrial creatine kinase function and activity, cardiac stem cells depletion and titin in sarcomeres.
Immune checkpoint inhibitors like atezolizumab (PD-L1), ipilimumab (CTLA-4), nivolumab (PD-1), durvalumab (PD-L1), permbrolizumab (PD-1), avelumabn (PD-L1) cause vasculitis and myocarditis through activation of immune Tcells.
Patients who consume therapeutic agents targeting tyrosine kinases: ABL directed, nilotinib, dasatinib and ponatinib may suffer from myocardial ischemia, systemic hypertension, cerebrovascular complications and venous thromboembolic disease. Suggested mechanisms for these abnormalities are, decrease of endothelial cell cAbl signaling and cell survival, reduction in VEGF-R2 signaling with attenuated endothelial proliferation, function and survival.
Cancer development and progression itself, can lead to cardiac wasting, fibrosis and vasculature thromboembolic events. Hence, tumor cells and their microenvironment express inflammatory cytokines, procoagulant factors, hormones, autophagy and ubiquitin-proteasome enzymes. Besides, cancer patients develop tumor lysis syndrome specially in leukaemia and lymphomas.
Cancer and cardiovascular disease (CVD), share risk factors comprising, smoking, sedentary lifestyle, obesity, hypertension, diabetes mellitus and pathophysiological mechanisms like oxidative stress, chronic inflammation and genetic contributors.
Cardiac dysfunction may also facilitate angiogenesis, tumor growth and invasiveness by increasing oxidative stress and secretion of pro-inflammatory factors and cardiokines.
Genetic
Recent studies emphasize that genetic factors have crucial role in the development of cardiotoxicities, resulting from cancer and its treatment and may illustrate why occur only in a subset of patient. cancer and CVD share genetic risk factors. patient with BRCA1/2 mutations also have coagulating problems. Altered levels of IGF-1 increase the risks of insulin resistance, contributing to CVD. Low levels of IGF-1 in individuals having only BRCA1/2 mutations, while high-level IGF-1 in breast cancer patients with BRCA1/2 mutations were observed. mutations of TTN are frequent in dilated cardiomyopathy and also demonstrated in 30% of solid tumors. researchers recruited TTN mutations to predict responses to immune checkpoint inhibitor immunotherapy. Through investigating shared genetic contribution for both disorders, an extremely interconnected network with a single subnetwork comprising 56 nodes and 146 edges were detected. TTN, ATM, JAK2, TET2 showed the highest number of disease interactions. The pathway enrichment analysis indicated that studied genes were significantly enriched in DNA damage repair pathways.
cardiotoxicities relevant to anthracycline have genetic basis. Various single nucleotide polymorphisms have demonstrated associations like, ABCC1 (rs3743527TT, rs246221TC/TT, rs3743527TT), SLC28A3 rs7853758, FMO2 rs2020870, SPG7 rs2019604, SLC10A2 rs9514091, SLC22A17 rs4982753, SLC22A7 rs4149178. Genotypes of rs2232228 in HAS3 showed different effects on anthracycline-induced cardiomyopathy risk. cardiomyopathy in patients with GG genotype, was uncommon and was not dose-dependent. When patient exposed to high dose anthracyclines, AA genotype demonstrated an 8.9-fold higher cardiomyopathy risk.
Non-coding RNAs also affect cardiotoxicities of cancer therapies. knockdown of lncRNA NEAT1 in human gastric cancer cells, which are resistant to doxorubicin, promoted apoptosis of doxorubicin-resistant cells. miR-22 is expressed in cardiac and skeletal muscles and is upregulated in doxorubicin treated cells. Inhibition of miR-22 reduces oxidative stress and apoptosis in cardiomyopathies. Therefore, targeting miR-22 may reduce doxorubicin cardiotoxicity.
Conclusion: Cardio-oncology revealed that molecular processes of cancer and cardiovascular diseases are intertwined and have improved our understanding of both disorders. However, identifying predictors of diseases risk, finding safer cancer therapeutics or cardioprotective drugs are the challenges in cardio-oncology.
Keywords: Cardio-oncology, Cardiovascular diseases, Cancer therapies, Genetic