Spasmogenic Effects of the Proteasome Inhibitor Carfilzomib on Coronary Resistance, Vascular Tone and Reactivity

Abstract

Background

Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials.

Aim of Study

To test the effects of CFZ (10 ^− 9 to 10 ^− 7 mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta.

Methods and Results

CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10 min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p < 0.05).

Conclusions

CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.

Highlights

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  In the isolated aorta, carfilzomib increased basal tone and vasospastic action of KCl, noradrenaline and angiotensin II.

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  In the isolated aorta, carfilzomib impaired the anti-spasmogenic activity of nitroglycerin, nifedipine and acetylcholine.

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  In the isolated heart, carfilzomib increased coronary perfusion pressure, and mildly left ventricular pressure and heart rate.

Carfilzomib is a new chemotherapeutic agent used for the treatment of multiple myeloma. Our study shows that carfilzomib increases coronary perfusion pressure, resting vasoconstricting tone, and the spasmogenic effect of noradrenaline and angiotensin II, while it curbs the vasodilatory action of nitroglycerine and nifedipine. Our findings are relevant to human health as they warrant caution in the use of carfilzomib in elderly patients with cardiovascular risk factors and, even more importantly, in those with preexisting heart conditions, who are also eligible to receive carfilzomib, even though they were excluded from the safety trials, based on which carfilzomib use was approved.