Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer

Abstract

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1–T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1–T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population.

Microvascular Structural Alterations in Cancer Patients Treated With Antiangiogenic Drugs

“…In our study, no change in mechanical properties of large arteries (distensibility, stiffness) was observed during treatment with VEGF inhibitor drugs, similar to what observed by Dalbeni et al ( 20 ). Similarly, no changes in cardiac structure and function were observed, except for a slight worsening of left ventricular relaxation.…”

“…A reduction of capillary density was previously observed in some ( 32 , 33 ), but not in other studies ( 20 ). In our study we did not observe any change in total capillary density during treatment, and no change was observed for basal or total capillary density in the nailfold.…”

“…Finally, it was suggested that treatment with VEGF inhibitors may increase large artery stiffness, increasing pulse wave velocity (PWV) ( 19 ), although the presence of an altered vascular distensibility was not confirmed in other studies ( 20 ).…”

Identification and Validation of Two Prognostic Autophagy-related Models in Clear Cell Renal Cell Carcinoma

“…Although there is a growing interest to use new rst-line treatment options as non-operative interventions or therapy protocols for ccRCC, including TKI cabozantinib, the immunotherapy combination of nivolumab /ipilimumab, and the combination of atezolizumab /bevacizumab, the individual prognosis of ccRCC is commonly less than satisfactory [4,6]. A number of lines of evidence suggested autophagy played an important role in cell survival, development, and cancer progression.…”

“…Not only African Americans but also Chinese have both a higher incidence and mortality rates for ccRCC [3]. Despite the rapidly evolving of experimental technologies and therapeutic guidelines in this eld, such as tyrosine kinase inhibitors (TKI) [4], optimized surgery [5] and immunotherapy [6], there is no curative treatment for advanced ccRCC. Therefore, it is warranted to develop candidate therapeutic biomarkers for improving survival of ccRCC patients.…”