Abstract 2401: Endothelial Dysfunction and Oxidative Stress in Human Coronary Microvasculature Following Acute Exposure to AL Amyloid Light Chains: New Mechanism of Amyloid Injury

Abstract

Light chain amyloidosis (AL), a plasma cell dyscrasia, is often fatal in patients with heart failure yet the mechanism of injury is unknown. We hypothesize that AL light chains (LC) acutely cause endothelial dysfunction in coronary arterioles. The aims are to measure endothelium-dependent and independent dilation and reactive oxygen species (ROS) in human coronary arterioles exposed to LC from AL subjects. Urine LC was isolated from 3 AL subjects by dialysis and lyophilization. Separately, 15 coronary arterioles were isolated from discarded atrial tissue from 12 non-AL subjects without significant vascular disease or diabetes undergoing open heart surgery (8 males, 70 ± 11 years). Arterioles were pressure-mounted and vessel diameter measured by videomicroscopy. Post-preconstriction with endothelin-1, vessels were exposed to vehicle and sequential doses of bradykinin (endothelium-mediated,10 −10 to 10 −6 M) then papaverine (endothelium-independent, 10 −4 M) were given and dilation was measured. Dilator response was again measured after 20 μg/mL of LC. Coronary arterioles were separately exposed to vehicle and LC and mitochondrial superoxide (MitoSox Red) and hydrogen peroxide (dichlorofluoroscein) were measured by fluorescence microscopy. see figure. Brief exposure to AL amyloid light chains impairs endothelium-dependent coronary vasodilation. This is associated with increased ROS production. This is the first human study demonstrating endothelial dysfunction in coronary microvasculature caused by AL LC. The vascular dysfunction and oxidative stress may be an important mechanism in the pathophysiology of this fatal disease.