The emerging role of endothelial function in cardiovascular oncology

The endothelium plays a central role in modulating vascular homeostasis, responding to physical and chemical signals by production of a wide range of factors that regulate vascular tone, cellular adhesion, thromboresistance, cell proliferation and vessel wall inflammation. In normal vascular physiology, endothelial cells maintain the vascular wall in a quiescent state by inhibition of inflammation, cellular proliferation, and thrombosis. When exposed to cardiovascular risk factors or, more generally, altered chemical and physical signals, they adopt a pro-atherosclerotic phenotype, characterised mainly by an increased secretion of substances with vasoconstricting, prothrombotic, proliferative and proinflammatory properties. At the microvascular level, this might lead to local dysregulation of the blood flow, potentially activating angiogenetic pathways that might result in the formation of new small vessels. Because of its central role in the neoangiogenesis and in the regulation of local blood flow, endothelial dysfunction and the disarray of newly formed vessels within the neoplastic mass are thought to play a key role in the abnormal intratumoral perfusion, leading to local hypoxia, impaired permeability, extracellular matrix degradation and efflux of cancer cells that ultimately result in a greater risk of metastatic diffusion (Figure 1). The key role of endothelial cells in regulating tumour physiology, including growth and dissemination, is confirmed by the results of clinical trials documenting a positive impact on cancer prognosis of novel antineoplastic agents that inhibits endothelial cell proliferation. In this issue of the European Journal of Preventive Cardiology, Toya et al. explore the prospective association between endothelial function, measured at the level of the microcirculation, and future risk of developing solid-tumour cancer. The authors enrolled a population of 687 patients who attended the Mayo Clinic for the assessment of chest pain and/or cardiovascular risk. The reactive hyperaemia peripheral arterial tonometry (RH-PAT) index was used to assess the presence of baseline microvascular endothelial dysfunction (MED), while blood tests and clinical history were collected to define the overall cardiovascular risk of the patients and the pre-existing presence of solid-tumour cancers. Following a median follow-up of six years, the authors assessed how many patients received a diagnosis of solid-tumour cancers, relating this information with the baseline presence of MED, defined as an RH-PAT index 2.0. At baseline, patients with MED had a much higher cardiovascular risk factor burden than patients without MED. The presence of MED at baseline, age and male sex were associated with an increased incidence of solid-tumour cancer during follow-up, and individuals with MED had a lower solid tumour cancer-free survival compared with individuals without MED. The association between MED and the risk of solid-tumour cancer remained significant even after adjustment for common cardiovascular risk factors and history of coronary artery disease. Based on these observations, the authors concluded that abnormal microvascular endothelial function may not only be considered a marker of future risk of cardiovascular disease but may also become a surrogate marker of the future cancer risk. The merit of this study is to explore a potential mechanism explaining the link between cardiovascular diseases and a higher incidence of cancer that has been suggested in previous observational studies and clinical trials. Particularly, the recent results obtained in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) suggests that an antiinflammatory treatment against interleukin (IL)-1b is able to improve cardiovascular outcome, as well as to reduce the incidence and mortality for cancer. The pathophysiological alterations underpinning the relationship between MED and incidence of cancer remain to be fully elucidated. While endothelial