Abstract 5253: Human Microvascular Dysfunction Induced by AL Amyloid Light Chain Proteins is Attenuated by Tetrahydrobiopterin
The mechanisms of injury in light chain (LC) amyloidosis (AL) remain unknown. We aim to measure endothelial/non-endothelial dilation and nitric oxide (NO) production in non-AL human coronary and adipose arterioles post exposure to LC±tetrahydrobiopterin (BH4).
Methods: Urine LC were purified (5 AL subjects, 57±11 years). Adipose (n=19) and coronary (n=25) arterioles from discarded fat and atrial appendage from non-AL patients post surgery were cannulated, pressurized (60 mm Hg) and dilation to acetylcholine (adipose:10−9–10−4M) or bradykinin (coronary:10−10–10−5M) and papaverine (both:10−4M) were measured before and 1 hour post exposure to LC (20 μg/mL) or LC+BH4 (100 μM). Separately, NO was measured using 4,5-diaminofluorescein diacetate fluorescence in arterioles exposed to LC, LC+BH4 and vehicle.
Results: Adipose arterioles had impaired dilation to acetylcholine (10−4M:47.4±8.2 versus 82.9±3.5% control, p=0.002) and papaverine (83.8±4.3 vs. 94.5±1.6% control, p=0.007) post-LC suggesting endothelial and non-endothelial dysfunction. Post LC, coronary dilation to bradykinin (10−5M:63.4±6.3 versus 84.8±3.1% control, p=0.004) but not papaverine was reduced signifying endothelial dysfunction. BH4 pretreatment restored adipose and coronary microvascular function (p=NS vs. control). NO production was reduced by LC but restored by BH4 (see figure⇓).
Conclusions: Brief exposure to AL light chains impaired microvascular function and reduced NO production in non-AL human adipose and coronary arterioles; both were restored by tetrahydrobiopterin. This novel mechanism of injury may be important in AL pathophysiology and a potential therapeutic target.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).