Abstract 12193: Cardiovascular Toxicity of Carfilzomib on Vascular Tone, Vascular Reactivity and Endothelial Function
Background: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of Multiple Myeloma (MM). Cardiac failure events (7.2%) and myocardial ischemia have occurred following administration CFZ. Infusion reactions also include chest thightness and angina of unknown mechanism.
Aim of study: To investigate whether CFZ exerts in vitro effects on vascular tone and reactivity in an isolated experimental model of rabbit thoracic aortic-strips.
Methods and Results: We evaluated first the effect of single injections of CFZ on the basal tone of isolated aortic strips (n= 6) placed in 10 ml organ bath at 37°C containing Krebs-Henseleit solution. Vasoconscriction, as documented by an overall increase in tension of 0.5 g, was observed with increasing concentrations of CFZ (from 1 x 10-9 to 10 -7 mol/L; p:0.041). In a second set of experiments, the effect of three different spasmogenic agents [potassium chloride (KCl) (n= 6), noradrenaline (NA) (n= 6), and angiontensin II (A) (n= 6)] on naive aortic strips (group 1) was compared to that on aortic strips pretrated for 60 minutes with CFZ at a concentration of 15 nmol/L (group 2). Pretreatment with CFZ resulted in amplified vasocostriction (2.4±0.4 g vs 2.1±0.3 g for KCl administration; 2.5±0.3 g vs 2.0±0.2 g for NA; 2.6±0.2 g vs 2.0±0.2 g for A; all p<0.005) and impaired vasodilation following administration of nitroglycerin (NTG) on the plateau of contraction induced by each spasmogenic agent (100% vs 82% for KCl; 100% vs 67% for NA and 100% vs 51% for A; all p<0.05). Finally, aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to naive strips (100 % versus 40% in tension reduction; p:0.028), following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction.
Conclusions: CFZ increased the resting vasoconstricting tone and amplified the spasmogenic effect of different agents. Moreover, preincubation with CFZ decreased the anti-spasmogenic activity of NTG and reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation by inducing endothelial dysfunction. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm.
Author Disclosures: T. Scarabelli: None. M. Gavazzoni: None. C. Chen-Scarabelli: None. G. Sahni: None. L. Saravolatz: None. J. Narula: None. R. Raddino: None.
- © 2014 by American Heart Association, Inc.