THE SPASMOGENIC ACTION OF THE PROTEASOME INHIBITOR CARFILZOMIB ON ARTERIAL AND VENOUS CONDUITS FROM PATIENTS UNDERGOING CORONARY ARTERY BYPASS GRAFT SURGERY IS ACCENTUATED BY PREEXISTING TYPE II DIABETES
Tiziano M. Scarabelli, M.D., Pauley Heart Center, Virginia Commonwealth University (VCU), Richmond, Virginia, USA
Carfilzomib (CFZ) is a proteasome inhibitor recently approved in the US for the treatment of relapsed/ refractory multiple myeloma. Its most severe side effects include sudden death, pulmonary hypertension, heart failure and myocardial ischemia. Angina of unknown mechanism was also reported. We previously shown that CFZ exerts powerful spasmogenic effects in isolated rabbit aortic strips. Of note, CFZ is not contraindicated in patients with recent myocardial infarction/unstable angina who were excluded from the phase II safety trials based on which CFZ approval was granted.
Aim of study: To investigate the effects of CFZ on vascular tone and reactivity of left internal thoracic artery (LITA) and saphenous vein (SV) specimens harvested during elective coronary artery bypass grafting (CABG).
Methods and Results: Of the 185 consecutive patients enrolled, 86 had type 2 diabetes (DMP) and 99 did not (NDMP). Specimens were spirally cut into vascular strips, subsequently immersed in an isolated organ bath. CFZ (10-9-10-7 mol/L) induced a dose-dependent increase in vessel tension, which was more pronounced in DMP (p<0.05). Nitroglycerin (NTG) and nifedipine (NFP) lessened, though not abolished, CFZ-induced vasoconstriction, with percentages of inhibition peaking at 62.2% and 49.4%, respectively, at their highest concentration (10-5 M). Pretreatment with CFZ amplified the spasmogenic effects of different agents, including KCl, noradrenaline (NA) and angiotensin 2 (A2), as well as curbed the vasodilatory response of NTG and NFP on the plateau of contraction induced by KCl, NA and A2 (p<0.01). Both effects were significantly more pronounced in DMP (p<0.05). Finally, the endothelium-dependent vasodilation induced by acetylcholine was dramatically reduced in all conduits pretreated with CFZ, especially in SV grafts from DMP (p<0.01).
Conclusions: CFZ exerts substantial spasmogenic effects on vascular tone and reactivity of arterial and venous conduits. Vasoreactivity to CFZ is increased in DMP possibly due to preexisting endothelial dysfunction. Further studies are warranted to establish the clinical safety of CFZ in patients with known CAD and/or history of coronary spasm.