A method for detecting thoracic aortic aneurysm (TAA) or predisposition to TAA in a subject comprises measuring the amount of tetrahydrobiopterin (H4B) present in the test sample; and comparing a measured amount of HUB to a standard amount of H4B. A decreased amount of H4B present in the test sample compared to the standard is indicative of TAA or predisposition to TAA. The method can further comprise identifying a candidate for further testing or monitoring for TAA, such as by ultrasound or by repeated testing for H4B after one or more designated intervals. The method can also further comprise prescribing treatment for TAA to the subject, such as with folic acid therapy, and/or DHFR therapy, including gene therapy, and other therapies effective for recoupling eNOS and/or therapies targeting uncoupled eNOS. Methods are also described for monitoring the efficacy of treatment of TAA, and for evaluating the severity of TAA or risk of TAA.