Microvascular Structural Alterations in Cancer Patients Treated With Antiangiogenic Drugs

Abstract

Objective: Antiangiogenic therapies (tyrosine kinase inhibitors-TKI and direct anti-VEGF monoclonal antibodies) are being increasingly used in the treatment of solid tumors; hypertension represents a common side effect of these agents. Several mechanisms are involved in the development of hypertension, including microvascular rarefaction and other microvascular alterations. Therefore, the aim of our study was to evaluate whether TKI and direct anti-VEGF agents may affect the structure of retinal arterioles or capillary density.Design and Methods: We investigated 20 patients with a diagnosis of cancer who underwent a treatment with either a TKI or an anti-VEGF antibody. Patients were submitted to ambulatory monitoring blood pressure for blood pressure evaluation. Basal and total capillary density were assessed by capillaroscopy whereas, retinal arteriole morphology was measured by Adaptive Optics. Patients were evaluated before starting the antiangiogenic therapy (T0) and re-evaluated after 3 (T3) and 6 (T6) months after treatment. Fourteen patients completed the study.Results: Systolic and diastolic blood pressure values were similar in all patients at T3 and T6 compared to T0. However, during the study antihypertensive treatment was optimized (increased dose and/or addition of drugs) in 57% of patients (n = 8). No differences were observed in retinal arteriole structural parameters and in large artery stiffness. Basal capillary density was reduced by antiangiogenic drugs after 3 or 6 months.Conclusions: Our data suggest that an increase of antihypertensive treatment is necessary in patients treated with a TKI or a direct VEGF inhibitor, confirming pro-hypertensive effects of these drugs. However, under adequate blood pressure control, microvascular structure seem to be partially preserved, since a worsening of basal capillary density but no changes in retinal arteriole morphology were observed.

The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation

“…Data are expressed as meanþstandard deviation. Adapted from [338] Microvascular inflammation in age-related diseases contributor to the ECs response to hypoxia, arrests impaired angiogenesis and reverts the PVAT to a browning phenotype, rescuing the MD and the whole-body metabolic homeostasis [158].…”

“…Another consequence of antiangiogenic drugs leading to vascular resistance increase and elevated blood pressure is microvascular rarefaction. A reduction of capillary density during antiangiogenic treatment, reversible with cancer drug discontinuation [335], was observed in some [336][337][338][339] but not in other studies [340]. In one of these studies [338], the effect of antiangiogenic drugs on the structure of retinal arterioles and capillary density was investigated in 20 patients with cancer.…”

“…A reduction of capillary density during antiangiogenic treatment, reversible with cancer drug discontinuation [335], was observed in some [336][337][338][339] but not in other studies [340]. In one of these studies [338], the effect of antiangiogenic drugs on the structure of retinal arterioles and capillary density was investigated in 20 patients with cancer. No change in systolic or diastolic blood pressure values during treatment was observed [338]; however, during the study, antihypertensive treatment was optimized in most patients.…”

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

“…19,32,75,76 Microvascular rarefaction may occur when antiangiogenic therapy reduces the microvascular surface area whilst increasing vascular resistance and blood pressure. 77 It was thought that chronic VEGF depletion leads to reduced microvascular endothelial cell survival and consequently reduced tissue microvascular density. 77 Formation of local thrombosis leads to a further decrease in vascular perfusion and exacerbates endothelial cell apoptosis and microvascular obliteration.…”

“…77 It was thought that chronic VEGF depletion leads to reduced microvascular endothelial cell survival and consequently reduced tissue microvascular density. 77 Formation of local thrombosis leads to a further decrease in vascular perfusion and exacerbates endothelial cell apoptosis and microvascular obliteration. These cumulative effects lead to increased systemic vascular resistance, resulting in a further increase in blood pressure.…”