Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis

Cardiovascular disease and cancer are the 2 leading causes of death worldwide. Emerging evidence suggests common mechanisms between cancer and cardiovascular disease, including atrial fibrillation and atherosclerosis. With advances in cancer therapies, screening, and diagnostics, cancer-specific survival and outcomes have improved. This increase in survival has led to the coincidence of cardiovascular disease, including atrial fibrillation and atherosclerosis, as patients with cancer live longer. Additionally, cancer and cardiovascular disease share several risk factors and underlying pathophysiologic mechanisms, including inflammation, cancer-related factors including treatment effects, and alterations in platelet function. Patients with cancer are at increased risk for bleeding and thrombosis compared with the general population. Although optimal antithrombotic therapy, including agent choice and duration, has been extensively studied in the general population, this area remains understudied in patients with cancer despite their altered thrombotic and bleeding risk. Future investigation, including incorporation of cancer-specific characteristics to traditional thrombotic and bleeding risk scores, clinical trials in the cancer population, and the development of novel antithrombotic and anti-inflammatory strategies on the basis of shared pathophysiologic mechanisms, is warranted to improve outcomes in this patient population.

Cancer and cardiovascular disease share common pathophysiology, including inflammation.
Thrombosis and bleeding risk scores often underperform in patients with cancer and cardiovascular disease.
Inclusion of cancer status in cardiovascular trials and risk scores may improve cardiovascular outcomes.      Diabetes is another classic risk factor for CAD that is also associated with an increased risk for malignancy, especially colorectal cancer. The risk for developing colorectal cancer was increased by 20% to 38% in patients with diabetes compared with those without (82).
Age is a significant risk factor for both cancer and CAD and is also associated with increased somatic mutations in hematopoietic progenitors, leading to clonal hematopoiesis of indeterminate potential (CHIP). These age-related mutations found in genes such as DNMT3A, TET2, JAK2, and ASXL1, although they are also found in myeloid neoplasms including myelodysplastic syndromes, acute myeloid leukemia, and myeloproliferative neoplasms, in CHIP, they do not cause alterations in peripheral blood counts (83).
CHIP is present in 10% of patients older than 70 years and confers a 10-fold increased risk for developing hematologic malignancy (83).  In summary: CHIP is a risk factor for both atherosclerosis and hematologic malignancies and may also be associated with worse outcomes in solid tumors.
Adverse effects of CHIP on cardiovascular outcomes and cancer may be due to inflammation.
Cancer-related treatments, including radiation, conventional cytotoxic chemotherapy, TKIs, and immunotherapy, can increase cardiovascular risk. ligand, IL-1b, platelet-derived growth factor, transforming growth factor-b, ROS, and P-selectin (114,120,121). Platelets have been shown to oxidize low-density lipoprotein, which is a major driver of atherosclerotic plaque formation (122,123). Additionally, platelets also promote monocyte migration to atherosclerotic plaques and induce their differentiation to an inflammatory phenotype, leading to plaque growth and foam cell formation (124,125). Platelets also interact with neutrophils and eosinophils to promote atherosclerotic plaque formation, growth, and thrombosis by inducing neutrophil extracellular trap or eosinophil extracellular trap formation, respectively (126)(127)(128). Increased platelet activation, as measured by urinary levels of 11-dehydro-thromboxane B 2 (a metabolite of thromboxane A 2 ), has also been associated with excess vascular risk in patients with AF despite oral anticoagulation (129).

ROLE OF PLATELETS AND
Platelets have an important role in cancer development, progression, and metastasis (117,119,130,131).
Thrombocytosis has been associated with worse outcomes in several types of cancer, including lung, colorectal, ovarian, and hepatocellular carcinoma (132)(133)(134)(135). Additionally, in a mouse model of metastatic lung cancer, induced thrombocytopenia led to significant improvement in survival (136). Tumors may also express proteins that bind to platelets, including podoplanin, which induces platelet aggregation through C-type lectin-like receptor 2 (CLEC-2) and facilitates hematogenous spread and thrombosis (137,138).  Common Cancer and Cardiovascular Disease Pathophysiology adenocarcinoma (153,154). Another large cohort study involving more than 18,000 patients showed that long-term aspirin use of more than 5 years was associated with a decreased incidence of colorectal cancer and prostate cancer in men (155). In addition to reduced risk for metastatic disease, aspirin may reduce the incidence of cancer and risk for cancer- with increased thrombotic risk (166). Lysyl oxidase is also a proangiogenic factor that promotes neoangiogenesis in some solid cancers by inducing vascular smooth muscle migration and proliferation (167). In atherosclerotic heart disease, lysyl oxidase has been found to be present in atherosclerotic lesions and to be associated with arterial restenosis after arterial balloon angioplasty (168)(169)(170). In myeloproliferative neoplasms, platelets have been shown to express lysyl oxidase, and increased lysyl oxidase activity is associated with increased platelet adhesion to collagen and increased arterial thrombus formation in a mouse model (166,171). In preclinical studies, inhibition of lysyl oxidase has been shown to attenuate progression of myelofibrosis, a myeloproliferative neoplasm, and triple-negative breast cancer and thus is a promising novel therapy (172)(173)(174).
In summary: Platelets improve the risk/benefit ratio of pharmacologic thromboprophylaxis (181,182).

The risk for thrombosis in patients with cancer
with AF has been studied in retrospective studies.
One study of elderly patients with AF found an increased risk for thromboembolic events in patients with lung cancer (183)  Common Cancer and Cardiovascular Disease Pathophysiology may be underused in this patient population (196)(197)(198). Patients with malignancy are less likely to undergo stenting, receive drug-eluting stents, receive newer generation P2Y 12 inhibitors (ticagrelor or prasugrel), and receive standard of care medications (beta-blockers, statins, or angiotensin-converting enzyme inhibitors) compared with those without cancer (193,194).
In summary: Patients with cancer and AF are at high risk for bleeding.
Risk for thrombosis in patients with cancer and AF is more heterogeneous, but certain cancer types ACKNOWLEDGMENT Figures 1 and 2 were created using BioRender. Extended duration of dual-antiplatelet therapy