No abstract

Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity.

Arterial stiffness, estimated by pulse wave velocity (PWV), is an independent predictor of cardiovascular mortality and morbidity. However, the clinical applicability of these measurements and the elaboration of reference PWV values are difficult due to differences between the various devices used. In a population of 50 subjects aged 20-84 years, we compared PWV measurements with three frequently used devices: the Complior and the PulsePen, both of which determine aortic PWV as the delay between carotid and femoral pressure wave and the PulseTrace, which estimates the Stiffness Index (SI) by analyzing photoplethysmographic waves acquired on the fingertip. PWV was measured twice by each device. Coefficient of variation of PWV was 12.3, 12.4 and 14.5% for PulsePen, Complior and PulseTrace, respectively. These measurements were compared with the reference method, that is, a simultaneous acquisition of pressure waves using two tonometers. High correlation coefficients with the reference method were observed for PulsePen (r ¼ 0.99) and Complior (r ¼ 0.83), whereas for PulseTrace correlation with the reference method was much lower (r ¼ 0.55). Upon Bland-Altman analysis, mean differences of values ± 2s.d. versus the reference method were À0.15 ± 0.62 m/s, 2.09 ± 2.68 m/s and À1.12±4.92 m/s, for PulsePen, Complior and PulseTrace, respectively. This study confirms the reliability of Complior and PulsePen devices in estimating PWV, while the SI determined by the PulseTrace device was found to be inappropriate as a surrogate of PWV. The present results indicate the urgent need for evaluation and comparison of the different devices to standardize PWV measurements and establish reference values.

This study has shown a possible independent role of NAFLD in determining arterial stiffness.