At the Heart of Chemotherapy: Unveiling the Impact of Proteasome Inhibitors on Vascular Function, Arterial Stiffness, and Cardiovascular Risk"

Proteasome inhibitors, including bortezomib and carfilzomib, play a critical role in managing relapsed or refractory multiple myeloma by promoting apoptosis. Despite their therapeutic benefits, emerging evidence links these agents to cancer therapy-related cardiovascular dysfunction (CTRCD). Bortezomib, a first-generation reversible inhibitor, and carfilzomib, a second-generation irreversible inhibitor, have been associated with adverse cardiovascular outcomes such as hypertension, cardiac arrhythmias, and heart failure. This study explored the effects of bortezomib and carfilzomib on both cardiac function—measured by left ventricular ejection fraction (LVEF)—and vascular health, assessed through arterial stiffness and vascular reactivity. The aim was to expand the current understanding of CTRCD related to proteasome inhibition and investigate arterial stiffness as a potential early marker of vascular remodeling. Twelve-week-old male C57BL/6J mice (n = 8 per group) were randomly assigned to receive either vehicle, carfilzomib (8 mg/kg I.P.), or bortezomib (0.5 mg/kg I.P.). Some groups were also treated with L-NAME (0.5 mg/kg) to induce hypertension. Cardiac and vascular assessments via echocardiography were conducted on days 0 and 3, and ex vivo analyses followed on day 6. Findings revealed no significant differences in arterial stiffness in vivo or ex vivo at baseline pressures. However, carfilzomib-treated mice exhibited a significantly steeper pressure-stiffness relationship ex vivo in both normotensive (p < 0.01) and hypertensive (p < 0.0001) conditions. In hypertensive mice, carfilzomib led to a reduction in LVEF (p = 0.06), with bortezomib showing a comparable trend. Vascular reactivity remained largely unaffected, though both drugs appeared to enhance endothelium-independent relaxation responses in control and hypertensive mice. In summary, short-term exposure to carfilzomib and bortezomib under the tested conditions appears to be relatively well-tolerated, though subtle cardiovascular changes warrant further investigation.