Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.

Myriad risk factors-including uncontrolled hypertension, aging, and diverse genetic mutations-contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.

Assessment of elastin deficit in a Marfan mouse aneurysm model using an elastin-specific magnetic resonance imaging contrast agent.

BACKGROUND: Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome. The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using MRI with a gadolinium-based elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) mice. METHODS AND RESULTS: Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (n=9 and n=10, respectively) using 7-T MRI with a T1 mapping sequence. Significantly lower enhancement (ie, lower R1 values, where R1=1/T1) was detected post-elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) compared with wild-type ascending aortas (1.15±0.07 versus 1.36±0.05; P<0.05). Post-elastin-specific magnetic resonance contrast agent R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (P=0.006). CONCLUSIONS: Herein, we demonstrate that MRI with elastin-specific magnetic resonance contrast agent accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared with wild-type controls. This approach has translational potential for noninvasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.

Cost associated with D-Dimer screening for acute aortic dissection.

INTRODUCTION: D-Dimer (DD) has been described as a useful predictor of both morphologic changes in acute thoracic aortic dissection (TAD) and of TAD-associated mortality. This study analyzed the use of DD screening to screen patients with chest pain for acute (TAD) to determine if it improves diagnosis and cost effectiveness. This study also looked at the association of DD levels with diagnoses frequently seen in patients with dyspnea or chest pain. METHODS: At the Helios Hospital, Krefeld, the authors analyzed the data of all patients (n = 1053, age (mean, SD) 62 ± 19 years, 49% males) admitted for chest pain to the nonsurgical emergency department (ED) in February 2010. Chest pain was the second most frequent symptom causing 138 (13.1%) admissions, 102 of which had DD testing (Inniovance® D-Dimer Assay, Dade Behring/Siemens, Germany). To assess the diagnostic reliability of DD testing, the sensitivity, specificity, and odds ratio, including 95% confidence interval, were estimated. RESULTS: None of the patients admitted were found to have acute TAD. Had the authors used a computerized tomography (CT) scan to rule out TAD in every patient with chest pain, actual costs would have been euro 12,328. A restriction of CT scans to patients with elevated DD levels would have lowered costs to euro 5360. The actual costs were euro 670.30 for CT scans and euro 540.60 for DD tests. On analyzing the association with other diagnoses, both sensitivity and specificity were low, with the exception of pneumonia. CONCLUSION: Owing to the low incidence of TAD, DD screening increases diagnostic efforts and costs but it remains unclear whether it would actually speed up TAD diagnosis. In a clinical setting DD did not help to discriminate other relevant diagnoses. Despite the high sensitivity of DD for aortic dissection published in the literature, the physician's clinical judgment remains paramount.