Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct:56:102444.
doi: 10.1016/j.redox.2022.102444. Epub 2022 Aug 17.

Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms

Yixuan Zhang  1 , Kin Lung Siu  1 , Qiang Li  1 , Kimberly Howard-Quijano  2 , Jennifer Scovotti  1 , Aman Mahajan  2 , Hua Cai  3
Affiliations

Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms

Yixuan Zhang et al. Redox Biol. 2022 Oct.

Erratum in

Abstract

We have previously shown that circulating levels of tetrahydrobiopterin (H4B) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating H4B levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating H4B levels were substantially lower in TAA and AAA patients, linearly correlated with aortic H4B levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379-0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385-0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125-0.868; p = 0.025) after adjustment for other factors. Blood or plasma H4B levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191-2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956-1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating H4B levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms.

Keywords: Abdominal aortic aneurysm (AAA); Aortic aneurysm; Biomarker; Diagnosis; Human patients; Monitoring; Prediction; Tetrahydrobiopterin (H(4)B); Thoracic aortic aneurysm (TAA); eNOS uncoupling.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Decreased circulating H4B levels in patients with TAA. Circulating levels of H4B were determined using HPLC as we previously published. Data indicate that circulating H4B levels were substantially reduced in (A) blood (n = 52 for control and n = 92 for TAA) and (B) plasma (n = 52 for control and n = 93 for TAA) samples of patients with TAA comparing to those of control subjects. ***p < 0.001.
Fig. 2
Fig. 2
Circulating H4B levels correlated linearly with aortic H4B levels in patients with TAA. Circulating levels of H4B were determined using HPLC as we previously published. Data indicate that (A) Blood (n = 75) and (B) plasma (n = 75) levels of H4B were linearly correlated with aortic H4B levels in patients with TAA. (C) Linear correlation between blood and plasma levels of H4B in both control and TAA patients (n = 145).
Fig. 3
Fig. 3
Patients with AAAhadreducedcirculating and aorticH4B levels,and elevated aortic eNOS uncoupling activity. Significantly reduced (A) blood (n = 44 for control and n = 25 for AAA) and (B) aortic (n = 44 for control and n = 29 for AAA) levels of H4B in patients with AAA comparing to control subjects. ***p < 0.001. (C) Activity of eNOS uncoupling, represented by l-NAME-sensitive superoxide production, was significantly elevated in patients with AAA (n = 42 for control and n = 24 for AAA). p = 0.003.
Fig. 4
Fig. 4
Both aortic and blood levels of H4B negatively correlated with aortic eNOS uncoupling activity in control subjects and AAA patients. (A) Blood H4B levels correlated linearly with aortic H4B levels in both control subjects and AAA patients (n = 69 total). Aortic eNOS uncoupling activity was negatively correlated with (B) aortic (n = 66) and (C) blood (n = 62) H4B levels.
See this image and copyright information in PMC

References

    1. Erbel R., Aboyans V., Boileau C., Bossone E., Bartolomeo R.D., Eggebrecht H., Evangelista A., Falk V., Frank H., Gaemperli O., Grabenwoger M., Haverich A., Iung B., Manolis A.J., Meijboom F., Nienaber C.A., Roffi M., Rousseau H., Sechtem U., Sirnes P.A., Allmen R.S., Vrints C.J., Guidelines ESCCfP ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC) Eur. Heart J. 2014;35:2873–2926. 2014. - PubMed
    1. Virani S.S., Alonso A., Benjamin E.J., Bittencourt M.S., Callaway C.W., Carson A.P., Chamberlain A.M., Chang A.R., Cheng S., Delling F.N., Djousse L., Elkind M.S.V., Ferguson J.F., Fornage M., Khan S.S., Kissela B.M., Knutson K.L., Kwan T.W., Lackland D.T., Lewis T.T., Lichtman J.H., Longenecker C.T., Loop M.S., Lutsey P.L., Martin S.S., Matsushita K., Moran A.E., Mussolino M.E., Perak A.M., Rosamond W.D., Roth G.A., Sampson U.K.A., Satou G.M., Schroeder E.B., Shah S.H., Shay C.M., Spartano N.L., Stokes A., Tirschwell D.L., VanWagner L.B., Tsao C.W. American heart association council on E, prevention statistics C and stroke statistics S. Heart disease and stroke statistics-2020 update: a report from the American heart association. Circulation. 2020;141:e139–e596. - PubMed
    1. Tellides G. Further evidence supporting a protective role of transforming growth factor-beta (TGFbeta) in aortic aneurysm and dissection. Arterioscler. Thromb. Vasc. Biol. 2017;37:1983–1986. - PMC - PubMed
    1. Hiratzka L.F., Bakris G.L., Beckman J.A., Bersin R.M., Carr V.F., Casey D.E., Jr., Eagle K.A., Hermann L.K., Isselbacher E.M., Kazerooni E.A., Kouchoukos N.T., Lytle B.W., Milewicz D.M., Reich D.L., Sen S., Shinn J.A., Svensson L.G., Williams D.M., American College of Cardiology Foundation/American Heart Association Task Force on Practice G, American Association for Thoracic S, American College of R, American Stroke A, Society of Cardiovascular A, Society for Cardiovascular A, Interventions, Society of Interventional R, Society of Thoracic S and Society for Vascular M ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American college of cardiology foundation/American heart association task force on practice guidelines, American association for thoracic surgery, American college of radiology, American stroke association, society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, society of interventional radiology, society of thoracic surgeons, and society for vascular medicine. Circulation. 2010;121:e266–369. 2010. - PubMed
    1. Kent K.C. Clinical practice. Abdominal aortic aneurysms. N. Engl. J. Med. 2014;371:2101–2108. - PubMed

Publication types

MeSH terms